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G Protein-Coupled Receptors

GPCR Products by Class• Class A: Rhodopsin-like• Class B: Secretin-like• Class C: Glutamate• Class F: Frizzled• GPCR Signaling

Opium PoppyPapaver somniferumA source of Morphine

Product Listing | Edition 1 | Euro

Tocris Product Listing Series

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ContentsThis listing contains over 450 products, including agonists, antagonists and allosteric modulators for a wide range of G protein-coupled receptors (GPCRs). GPCRs are divided into their respective classes: Rhodopsin-like (class A), Secretin-like (class B), Glutamate (class C) and Frizzled (class F). Products for GPCR signaling are also listed.

Class A: Rhodopsin-like 4

Class A1/A2 4CCChemokineReceptorsCXCChemokineReceptors

GPCR Crystal Structures 5

Class A2 6Estrogen(GPER)Receptors

Class A3 6AngiotensinReceptorsApelinReceptorsBradykininReceptors

Class A4 6OpioidReceptorsNeuropeptideW/BReceptorsSomatostatinReceptors

Class A5 7GalaninReceptorsKisspeptinReceptorsLeukotrieneReceptorsMelanin-concentratingHormone(MCH)ReceptorsUrotensin-IIReceptors

Class A6 8CholecystokininReceptorsGnRHReceptorGPR103OrexinReceptorsOxytocinReceptorVasopressinReceptors

Class A7 9BombesinReceptorsEndothelinReceptorsGhrelinReceptorMotilinReceptorNeuromedinUReceptorsNeurotensinReceptorsThyrotropin-ReleasingHormoneReceptors

Class A8 10FormylPeptideReceptors

Class A9 10MelatoninReceptorsNeuropeptideYReceptorsTachykininReceptors

Class A11 11FreeFattyAcidReceptorsHydroxycarboxylicAcidReceptors

Class A11/12 11PurinergicReceptors

Class A12 12Platelet-activatingFactorReceptor

Class A13 12CannabinoidReceptorsMelanocortinReceptorsSphingosine-1-phosphateReceptors

Class A13/15 13LysophosphatidicAcidReceptors

Class A14 14ProstanoidReceptorsThromboxane(TP)Receptors

Class A15 14GPR35Protease-activatedReceptors

Class A17 15AdrenergicReceptorsDopamineReceptorsTraceAmine1Receptor

Class A17/18 17HistamineReceptors

Class A17/19 185-HTReceptors

Class A18 19AdenosineReceptorsAcetylcholineMuscarinicReceptors

Other GPCRs 21NeuropeptideFF/AFReceptorsOrphanGPCRsSensoryNeuron-specificReceptors

DREADD Ligands 21

Class B: Secretin-like 22

CalcitoninandRelatedReceptorsCorticotropin-releasingFactorReceptorsGIPReceptorGlucagonReceptorGlucagon-LikePeptideReceptorsPACAPReceptorParathyroidHormoneReceptorsSecretinReceptorVIPReceptors

Class C: Glutamate 24

Calcium-sensingReceptorGABABReceptorsGlutamate(Metabotropic)Receptors

GPCR Allostery 27

Class F: Frizzled 28

SmoothenedReceptor

GPCR Signaling 29

AdenylylCyclasecAMPGProtein(Heterotrimeric)GRKIP3ReceptorPhospholipases

Bias Signaling 30

ReferencesandFurtherReading 31

GPCR ReSeaRCh

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IntroductionGPCRs are transmembrane receptors that mediate signal transduction from the cytosol to the cell interior. There are approximately 850 known GPCRs, which make up the largest receptor superfamily. GPCRs can be classified according to their structural and functional relationship, as represented by the ‘GPCR Tree’.

GPCR Tree Gene AbbreviationsADORA, adenosine receptor; ADR, adrenergic receptor; AGTR, angiotensin receptor; AGTRL1, apelin receptor; AVPR, vasopressin receptor; BDKRB, bradykinin receptor; BRS3, bombesin-like receptor 3; CALCR, calcitonin receptor; CASR, calcium sensing receptor; CCKR, cholecystokinin receptor; CCR, CC chemokine receptor; CHRM, acetylcholine muscarinic receptor; CNR, cannabinoid receptor; CRHR, corticotropin-releasing factor receptor; CXCR, CXC chemokine receptor; CYSLTR, cysteinyl leukotriene receptor; DRD, dopamine receptor; EBI2, eBV-induced G-protein coupled receptor 2; S1PR, sphingosine-1-phosphate receptor; EDNR, endothelin receptor; FPR, formyl peptide receptor; GABBR, GaBaB receptor; GALR, galanin receptor; GCGR, glucagon receptor; GHSR, ghrelin receptor; GIPR, GIP receptor; GLPR, glucagon-like receptor; GNRHR, gonadotropin-releasing hormone receptor; GPR, G-protein coupled receptor; GRM, glutamate receptor metabotropic; GRPR, gastrin-releasing peptide receptor; HCRTR, orexin receptor; HRH, histamine receptor; HTR, 5-hT receptor; LPAR, lysophosphatidic acid receptor; MCR, melanocortin receptor; MCHR, melanin-concentrating hormone receptor; MRGX1 (SNSR1), sensory neuron-specific receptor; MLNR, motilin receptor; MLNR, melatonin receptor; NMBR, neuromedin receptor; NMUR, neuromedin U receptor; NPFFR, neuropeptide FF receptor; NPYR, neuropeptide Y receptor; NTSR, neurotensin receptor; OPR, opioid receptor, OXTR, oxytocin receptor; P2YR, purinergic receptor; PACAPR, pituitary adenylate cyclase-activating polypeptide; PAR, protease-activated receptor; PTAFR, platelet-activating factor receptor; PTGER, prostaglandin e2 receptor; PTGFR, prostaglandin F2 receptor; PTGIR; prostacyclin receptor; PTHR, parathyroid hormone receptor; SCTR, secretin receptor; SMOH, smoothened receptor; SSTR, somatostatin receptor; TACR; tachykinin receptor; TAR1, trace amine 1 receptor; TBXA2R, thromboxane a2 receptor; TRHR, thyrotropin-releasing hormone receptor; UR2R, urotensin receptor; VIPR, vasoactive intestinal peptide

A Representation of the GPCR Tree Featuring Genes of GPCRs Targeted by Tocris Products

ADRA2

CHRM1CHRM1

CHRM1

CHRM1

CHRM1

DRD2

DRD3DRD4

TBXA2R

ADRA1

HTR2ADRB1

DRD5

MLNR

DRD1

ADRB2

ADRB3

S1PR LPAR

CNR1 CNR2

MCR

ADORA2B

ADORA2A

ADORA3 ADORA1

EDNRB

EDNRA

BRS3 GRPR

NMBR

HCRTR1

HCRTR

CCKAR

CCKBR

NPFFR TACR2

TACR1

TACR3NPYR

NTSR

NMUR

MTLR

GHSR

GHRHR

GABBR

CASR

GRM1GRM5

GRM3

GRM2

GRM6GRM4

GRM7GRM8

CALCR

SMOH

SCTR

VIPRCRH1

CRH1PTHR

PACAPR

GLPR

GIPR

GCGR

OXTR

AVPR

GNR

HTR7

HTR6

HTR4

TAR1

PTGFR

PTGER1

PTGIR

CYSLTR

AGTRL1

FPR1

BLTR

BDKBR

AGTR1CCR

CXCRGPR7

OPRL

OPRK

OPRM

OPRD

GALR

MCHR

UR2R

SSTRGPR54

GPR17

P2YR

GPR55

GPR35

PAR

GPR103 PTAFR EBI2 TRHR

MRGX1 (SNSR1)

HRH4 HRH3

HRH2 HRH1

HTR5

HTR1 Class A – Rhodopsin-like

Class B – Secretin-like

Class C – Glutamate

Class F – Frizzled

adapted from Raymond et al (2013) Nat.Rev.Drug Discov. 12 25.


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Class a: Rhodopsin-likeThe Rhodopsin-like receptors are the largest class within the GPCR superfamily, being characterized by certain conserved amino acid residues in their transmembrane helices. Class A receptors have a wide variety of ligands including, neurotransmitters, peptides, glycoproteins, steroid hormones and lipids.

CXCR4 in Complex with IT1t Crystal Structure of the CXCR4 Homodimer in Complex with the CXCR4 Antagonist IT1t

Image adapted from the RSCB PDB (www.rcsb.org) of PDB ID: 3Oe9 Wu et al (2010) Science 330 1066. PMID 20929726.

•IT1tbindstopartofthebindingcavityofCXCR4andinteractswithsidechainsfromhelicesI,II,IIIandVII

•IT1tisapotentCXCR4antagonist(IC50=1.1nM)

•Thecompoundisorallyavailable

Cat. No. 4596

CXCR4 – IT1t

NN

S

SN

NH

B2-Adrenergic – ICI 118,551

NHHO

O

A2A – ZM 241385

OH

NH

N

N N

N

NO

NH2

D3 – Eticlopride

H1 – Doxepin

O

N

CRF1R – CP-376395

N

O NH

3212

4596 0508

0821

1036MGLUR1 – LY 341495

O

CO2HH2N

OHO

1209

1847

N NH

O HO

OCl

Class A1/A2: CC Chemokine Receptors

Antagonists 3129 BMS CCR2 22 high affinity, potent CCR2 antagonist 1 mg

10 mg

50 mg

125

245

980

2595 J 113863 Potent CCR1 antagonist 1 mg

10 mg

50 mg

100

195

760

5176 JNJ 27141491 Potent and selective human CCR2 antagonist 10 mg

50 mg

225

900

3756 Maraviroc Selective CCR5 antagonist 10 mg

50 mg

215

865

2089 RS 102895 CCR2b antagonist 10 mg

50 mg

145

530

2517 RS 504393 highly selective CCR2 antagonist 10 mg 195

3650 SB 328437 Potent and selective CCR3 antagonist 10 mg

50 mg

165

635

CXC Chemokine Receptors

Agonists 4780 VUF 11207 Potent CXCR7 (aCKR3) agonist 10 mg

50 mg

195

775

5668 VUF 11222 high affinity non-peptide CXCR3 agonist 10 mg

50 mg

145

560

Antagonists 3299 aMD 3100 highly selective CXCR4 antagonist 10 mg

50 mg

145

545

4179 aMD 3465 Potent, selective CXCR4 antagonist 10 mg

50 mg

195

760

4487 (±)-aMG 487 CXCR3 antagonist; inhibits cell migration and metastasis 10 mg

50 mg

225

900

5130 CTCe 9908 CXCR4 antagonist; antitumor 1 mg 210

4596 IT1t Potent CXCR4 antagonist 10 mg

50 mg

175

665

Category Cat. No. Product Name Description Unit Size Euro

GPCR ReSeaRCh

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Class a: Rhodopsin-like – continued

GPCR Crystal StructuresCrystallography refers to the study of atomic and molecular structure. The elucidation of molecular structures of membrane proteins such as GPCRs has proven problematic, and only a small fraction of known GPCRs have been solved to date. GPCR crystal structures are invaluable for structure-based drug discovery approaches.

GPCR Crystal Structures and Drug Discovery:

The solving of GPCR crystal structures has been notoriously difficult, due to their flexible conformations. For their structure to be solved GPCRs need to be embedded in a membrane-like environment to maintain their structural integrity. This was difficult to achieve until the last decade, when certain mutations were found to increase GPCR stability and expression levels, while stabilization antibodies can also enhance GPCR stability.

The first GPCR structure to be crystallized was the Rhodopsin receptor in 2000, and receptor stabilization techniques resulted in the discovery of the adenosine a2a receptor and adrenergic β1 and β2 receptors in 2008. To date 26 GPCR structures have been solved (see table below). GPCR crystal structures could prove to be essential for next generation drug discovery. These structures can be utilized by automated computational screens for the identification of novel ligands and chemotypes, which could produce lead compounds for the synthesis of next generation drugs and enhanced therapeutics.

GPCR Crystal Structure Table

Table listing GPCRs whose crystal structures have been solved to date. Where the structure has been solved in complex with a ligand, the ligand is also listed. Ligands in bold are available from Tocris. The PDB-ID is the crystal structures PDB-ID from the RCSB PDB (www.rcsb.org/pdb). Data from zhanglab.ccmb.med.umich.edu/GPCR-eXP.

GPCR Species Ligand PDB-ID Reference

acetylcholine Muscarinic M2 Receptor human Iperoxo 4MQS Kruse et al (2013) Nature 504 101

acetylcholine Muscarinic M3 Receptor Rat Tiotropium (#5902) 4U15 Thorsen et al (2014) Structure 22 1657

adenosine a2a Receptor human

Adenosine (#3624) 2YDO Jaakola et al (2008) Science 322 1211

NECA (#1691) 2YDVLebon et al (2011) Nature 474 521

ZM 241385 (#1036) 3eML

adrenergic β1 Receptor Turkey

Cyanopindolol (#0993) 2VT4

Warne et al (2008) Nature 454 486Dobutamine (#0515) 2Y00

Isoprenaline (#1747) 2Y03

Salbutamol (#0634) 2Y04

adrenergic β2 Receptor humanICI 118,551 (#0821) 3NY8 Wacker et al (2010) J.Am.Chem.Soc 132 11443

Timolol (#0649) 3D4S hanson et al (2008) Structure 16 897

Chemokine CCR5 Receptor Maraviroc (#3756) 4MBS Tan et al (2013) Science 341 1387

Chemokine CXCR1 Receptor human - 2LNL Park et al (2012) Nature 491 779

Chemokine CXCR4 Receptor human IT1t (#4596) 3Oe6 Wu et al (2010) Science 330 1066

Corticotropin-releasing Factor Receptor 1 CP 376395 (#3212) 4K5Y hollenstein et al (2013) Nature 499 438

Dopamine D3 Receptor human Eticlopride (#1847) 3PBL Chien et al (2010) Science 330 1091

Free Fatty acid Receptor 1 TaK-875 4PhU Srivastava et al (2014) Nature 513 124

Glucagon Receptor human - 4L6R Siu et al (2013) Nature 499 444

histamine h1 Receptor human Doxepin (#0508) 3RZe Shimamura et al (2011) Nature 475 65

5-hT1B Dihydroergotamine (#0475) 4IaQ Wang et al (2013) Science 340 610

5-hT2B ergotamine 4IB4 Wacker et al (2013) Science 340 615

Metabotropic Glutamate Receptor 1 LY 341495 (#1209) 3KS9 Dobrovetsky et al (Data yet to be published)

Neurotensin Receptor Neurotensin (#1909) 4GRV White et al (2012) Nature 490 508

κ Opioid Receptor human JDTic 4DJh Wu et al (2012) Nature 485 327

μ Opioid Receptor β-Funaltrexamine (#0926) 4DKL Manglik et al (2012) Nature 485 321

δ Opioid Receptor Naltrindole (#0740) 4eJ4 Granier et al (2012) Nature 485 400

OX2 Orexin Receptor human Suvorexant 4S0V Yin et al (2015) Nature 519 247

Protease-activated Receptor 1 human Vorapaxar 3VW7 Zhang et al (2012) Nature 492 387

Purinergic P2Y12 Receptor 2MeSADP (#1624) 4PXZ Zhang et al (2014) Nature 509 119

Rhodopsin Receptor Bovine 11-cis-Retinal 1F88 Palczewski et al (2000) Science 289 739

Smoothened Receptor humanCyclopamine (#1623) 4O9R Wang et al (2014) Nat.Commun. 5 4355

SANT-1 (#1974) 4N4W Weierstall et al (2014) Nat.Commun. 5 3309

Sphingosine-1 Phosphate Receptor ML 056 (3602) 3V2W hanson et al (2012) Science 335 851


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4528 (±)-NBI 74330 Potent and selective CXCR3 antagonist 10 mg 255

5660 NVP CXCR2 20 Potent and selective CXCR2 antagonist 10 mg

50 mg

145

560

2725 SB 225002 Potent and selective CXCR2 antagonist 10 mg

50 mg

180

720

2724 SB 265610 Potent CXCR2 antagonist 1 mg

10 mg

50 mg

100

195

760

4300 TC 14012 CXCR4 antagonist; also CXCR7 (aCKR3) agonist 1 mg 215

Class A2 Estrogen (GPER) Receptors

Agonists 3577 G-1 Potent and selective GPeR agonist 10 mg

50 mg

180

720

1047 ICI 182,780 high affinity GPeR agonist 1 mg

10 mg

50 mg

100

195

760

Antagonists 3678 G-15 high affinity and selective GPeR antagonist 10 mg

50 mg

180

720

Class A3 Angiotensin Receptors

Agonists 1158 angiotensin II Potent vasoconstrictor peptide 5 mg 125

5728 eXP 3174 Potent and selective aT1 antagonist 10 mg

50 mg

130

485

Antagonists 5798 Irbesartan Potent aT1 antagonist 50 mg 100

3798 Losartan potassium Selective, non-peptide aT1 antagonist 50 mg 110

1361 PD 123319 Potent, selective non-peptide aT2 antagonist 10 mg

50 mg

195

760

Apelin (APJ) Receptors

Agonists 2420 [Pyr1]-apelin-13 Potent peptide agonist for aPJ receptor 1 mg 175

3007 apelin-17 (human, bovine) endogenous aPJ receptor agonist 1 mg 225

2426 apelin-36 (human) endogenous aPJ receptor agonist 1 mg 400

Antagonists 4748 ML 221 aPJ receptor antagonist 10 mg

50 mg

180

720

Bradykinin Receptors

Agonists 3004 Bradykinin endogenous agonist at bradykinin receptors (B2 > B1) 5 mg 85

Antagonists 3014 hOe 140 Potent and selective B2 antagonist 500 µg 195

Class A4 δ Opioid Receptor

Agonists 0764 SNC 80 highly selective non-peptide δ agonist 10 mg

50 mg

195

760

Antagonists 0740 Naltrindole Selective non-peptide δ antagonist 10 mg

50 mg

145

520

κ Opioid Receptor

Agonists 3195 Dynorphin a endogenous κ agonist 1 mg 200

5519 (-)-Pentazocine κ agonist; antinociceptive 10 mg 100

0496 (-)-U-50488 Standard selective κ agonist; more active enantiomer of (±)-U-50488 (Cat. No. 0495)

10 mg

50 mg

145

560

0495 (±)-U-50488 Standard selective κ agonist 25 mg 145

Antagonists 0347 nor-Binaltorphimine Standard selective κ antagonist 10 mg

50 mg

160

600

GPCR ReSeaRCh

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μ Opioid Receptor

Agonists 1171 DaMGO Selective μ agonist 1 mg 80

Antagonists 1560 CTaP Selective and potent μ antagonist 1 mg 145

2601 Cyprodime Selective μ antagonist 10 mg 195

0926 β-Funaltrexamine Irreversible μ-selective antagonist 10 mg

50 mg

195

760

Opioid Receptors (Non-selective)

Agonists 5158 Morphine Narcotic opioid analgesic 50 mg 100

1419 Naloxone benzoylhydrazone Full κ agonist; partial μ and δ agonist 10 mg

50 mg

125

445

Antagonists 0599 Naloxone Broad spectrum opioid receptor antagonist 100 mg 100

0677 Naltrexone Broad spectrum opioid receptor antagonist 100 mg 100

Neuropeptide W/B Receptors

Agonists 3009 Neuropeptide W-23 (human) endogenous NPBW1 and NPBW2 agonist 1 mg 245

Antagonists 4948 CYM 50769 Novel non-peptide NPBWR1 antagonist 10 mg

50 mg

180

720

Somatostatin (sst) Receptors

Agonists 1979 L-803,087 Potent and selective sst4 agonist 10 mg 270

1818 Octreotide sst2, sst3 and sst5 agonist 1 mg 245

1157 Somatostatin Influences growth hormone release 1 mg 110

Antagonists 3493 Cyclosomatostatin Non-selective sst receptor antagonist 1 mg 175

1843 CYN 154806 Selective sst2 antagonist 1 mg 225

Class A5 Galanin Receptors

Agonists 2696 Galanin (1-29) (rat, mouse) Non-selective galanin receptor agonist 1 mg 200

1179 Galanin (1-30) (human) endogenous galanin receptor agonist 200 µg 180

Kisspeptin Receptor

Agonists 2570 Kisspeptin 10 (human) endogenous kisspeptin receptor ligand 1 mg 275

4243 Kisspeptin 10 (rat) endogenous kisspeptin receptor ligand 1 mg 160

Leukotriene Receptors

Agonists 2307 Leukotriene B4 BLT1/BLT2 receptor agonist and potent chemotactic factor 50 µg 325

Antagonists 2338 MK 571 Potent CysLT1 (LTD4) inverse agonist; also MRP1 inhibitor 10 mg 175

Other 1311 MK 886 Inhibitor of 5-lipoxygenase-activating protein (FLaP) 10 mg

50 mg

180

720

Melanin-concentrating Hormone (MCH) Receptors

Agonists 3806 MCh (human, mouse, rat) Potent endogenous MCh receptor agonist 100 µg 85

Antagonists 4242 GW 803430 MCh1 antagonist 10 mg

50 mg

215

865

4365 TC-MCh 7c Selective MCh1 antagonist 10 mg 245

Urotensin-II (UT) Receptor

Agonists 2484 (±)-aC 7954 Non-peptide UT receptor agonist 10 mg

50 mg

180

720

1642 Urotensin II (human) endogenous vasoactive agonist for the UT receptor 1 mg 245

Antagonists 5110 GSK 1562590 high affinity, selective UT receptor antagonist 10 mg

50 mg

245

980

3571 SB 657510 Selective UT receptor antagonist 10 mg

50 mg

190

740

4667 SB 706375 high affinity, non-peptide UT receptor antagonist 10 mg

50 mg

180

720



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Orexin Receptors

ACT 462206 (5319)Potent, dual orexin receptor antagonist

EMPA (4558)Highly potent and selective OX2

antagonist; brain penetrant

SB 674042 (4673)Potent and selective non-peptide OX1 antagonist

IPSU (5645)OX2 antagonist; orally bioavailable

and brain penetrant

HN

O

N

SO

O

O

N

N

O

NS

N

OMe

O O

N

O

O

NN

S

N

F

N

NO N

N

O

NH

Featured Orexin Receptor Antagonists


Class A6 Cholecystokinin (CCK) Receptors

Agonists 2411 a-71623 Potent and selective CCK1 agonist; suppresses feeding 1 mg 255

1166 CCK Octapeptide, sulfated C-terminal octapeptide of CCK 1 mg 245

3006 Gastrin I (human) Selective CCK2 agonist 1 mg 275

Antagonists 2607 CI 988 Potent and selective CCK2 antagonist 10 mg

50 mg

255

1015

2304 Devazepide Selective CCK1 antagonist; orally active 10 mg

50 mg

225

900

Gonadotropin-releasing Hormone (GnRH) Receptor

Agonists 3592 Goserelin GnRh receptor agonist 10 mg 160

Antagonists 3536 Cetrorelix Potent GnRh receptor antagonist 1 mg 195

2519 T 98475 GnRh receptor antagonist 1 mg 215

GPR103

Ligands 4402 26RFa Ligand of GPR103; orexigenic neuropeptide 1 mg 195

Orexin Receptors

Agonists 1455 Orexin a (human, rat, mouse) endogenous agonist at OX1 and OX2 500 µg 445

2142 [ala11,D-Leu15]-Orexin B Potent, selective OX2 receptor agonist 1 mg 305

1456 Orexin B (human) endogenous agonist at OX1 and OX2 500 µg 270

1457 Orexin B (mouse) endogenous agonist at OX1 and OX2 500 µg 270

Antagonists 4983 aCT 335827 Potent and selective OX1 antagonist 10 mg

50 mg

290

1170

5319 aCT 462206 Potent, dual orexin receptor antagonist 10 mg

50 mg

200

795

4558 eMPa highly potent and selective OX2 antagonist; brain penetrant 10 mg

50 mg

210

820

5645 IPSU OX2 receptor antagonist; orally bioavailable and brain penetrant 10 mg 195

4317 JNJ 10397049 Selective OX2 receptor antagonist 10 mg

50 mg

195

760

GPCR ReSeaRCh

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Potent and Selective Motilin Receptor Antagonist

MA 2029 Cat. No. 4934

MA2029isapotentandselectivemotilinreceptorantagonist(IC50=4.9nM)thatexhibitsselectivityforthemotilinreceptoroverarangeofotherreceptorsandionchannels.Thecompoundinhibitsmotilin-inducedcolonicandabdominalcontractionsin vivo.MA2029isalsoorallyactive.

JNJ 27141491 (Cat. No. 5176)

N

F

F NHS

OOMe

O N

ML 00253764 (4854)

Br

OMe

F

NHN

TC-G 1008 (5355)

BIBN 4096 (4561)

N

N

N

NH

NH

Cl

NH

SOO

NHN

N

HNO

O

HN

N N NO O

NH2

Br

Br

HO

Purmorphamine (4551)

N

N N

N

NH

O

N

O

CMPD101 (5642)

N

N N

NNH

O

HN

F3C

MA 2029 (4934)

F

N

O

NH

ONHO

HN

OH



1960 SB 334867 Selective non-peptide OX1 antagonist 1 mg

10 mg

50 mg

100

195

760

4673 SB 674042 Potent and selective non-peptide OX1 antagonist 10 mg

50 mg

285

1130

3371 TCS OX2 29 Potent and selective OX2 antagonist 10 mg

50 mg

195

760

Oxytocin Receptor

Agonists 1910 Oxytocin endogenous oxytocin receptor agonist 1 mg 80

3933 WaY 267464 Potent non-peptide oxytocin receptor agonist 10 mg 240

Antagonists 2641 L-368,899 Potent, non-peptide oxytocin receptor antagonist 1 mg

10 mg

145

285

2410 L-371,257 Potent and selective oxytocin receptor antagonist 10 mg 215

Vasopressin Receptors

Antagonists 2310 SR 49059 Selective, orally active V1a receptor antagonist 10 mg 305

5181 Tolvaptan Potent and selective V2 receptor antagonist; renoprotective and orally active

10 mg

50 mg

160

600

Class A7 Bombesin Receptors

Agonists 5600 Ba 1 Potent BRS-3 agonist; also NMBR and GRPR agonist 1 mg 195

1789 GRP (human) endogenous GRP receptor agonist 1 mg 245

Antagonists 5599 ML 18 BRS-3 antagonist; also GRPR agonist 10 mg 255

Endothelin (ET) Receptors

Agonists 1189 BQ-3020 Selective eTB agonist 500 µg 215

1160 endothelin 1 (human, porcine) endogenous endothelin receptor agonist 100 µg 180

Antagonists 1188 BQ-123 Selective eTa antagonist 500 µg 175

1500 BQ 788 sodium salt Selective eTB antagonist 1 mg 290

1838 IRL-2500 Potent eTB antagonist 10 mg 240

Ghrelin Receptor

Agonists 1463 Ghrelin (human) endogenous ghrelin receptor agonist 1 mg 370

1465 Ghrelin (rat) endogenous ghrelin receptor agonist 1 mg 405

5272 MK 0677 high affinity ghrelin receptor agonist 10 mg

50 mg

145

560

Antagonists 1922 [D-Lys3]-GhRP-6 Ghrelin receptor antagonist 5 mg 140

3959 YIL 781 Ghrelin receptor (GhS-R1a) antagonist 10 mg

50 mg

200

795

Motilin Receptor

Agonists 2264 Motilin (human, porcine) endogenous motilin receptor agonist 1 mg 275

Antagonists 5074 aNQ 11125 Selective motilin receptor antagonist 1 mg 180

4934 Ma 2029 Potent and selective motilin receptor antagonist; orally active

10 mg

50 mg

210

820


10 |

Neuromedin U (NMU) Receptors

Agonists 3648 Neuromedin S (rat) Potent, endogenous NMU1 and NMU2 agonist 500 µg 285

1917 Neuromedin U (rat) endogenous modulator of blood pressure and flow, gut ion transport, feeding and body temperature

1 mg 200

Neurotensin (NTS) Receptors

Agonists 1909 Neurotensin endogenous neurotensin receptor agonist 1 mg 80

5087 TC NTR1 17 Selective non-peptide NTS1 agonist 10 mg

50 mg

225

900

Antagonists 2309 SR 142948 highly potent NT receptor antagonist 1 mg

10 mg

130

255

3721 SR 48692 Selective non-peptide NTS1 antagonist 10 mg

50 mg

245

980

Thyrotropin-Releasing Hormone Receptors

Agonists 2672 Taltirelin Synthetic thyrotropin-releasing hormone analog 1 mg

10 mg

115

215

Class A8 Formyl Peptide Receptors (FPRs)

Agonists 5583 Quin C1 Potent and selective FPR2 agonist 10 mg

50 mg

175

680

4624 TC-FPR 43 Potent FPR2 agonist 10 mg

50 mg

175

680

Antagonists 2262 WRW4 Selective FPR2 antagonist 1 mg 100

Class A9 Melatonin (MT) Receptors

Agonists 0737 2-Iodomelatonin high affinity melatonin receptor agonist 10 mg

50 mg

80

245

0680 2-Phenylmelatonin Potent melatonin receptor agonist 10 mg

50 mg

140

505

Antagonists 0877 Luzindole MT1/MT2 antagonist 10 mg

50 mg

145

560

1034 4-P-PDOT MT2 antagonist 10 mg

50 mg

145

530

Neuropeptide Y (NPY) Receptors

Agonists 1153 Neuropeptide Y (human, rat) endogenous NPY receptor agonist 200 µg 145

Antagonists 2412 BIBO 3304 highly selective NPY Y1 receptor antagonist 10 mg

50 mg

285

1130

2707 BIBP 3226 Mixed NPY Y1 and NPFF receptor antagonist 1 mg

10 mg

140

270

1700 BIIe 0246 Potent, selective non-peptide NPY Y2 receptor antagonist 1 mg

10 mg

145

290

4018 JNJ 5207787 Selective NPY Y2 receptor antagonist 10 mg

50 mg

240

935

Tachykinin (NK) Receptors

Agonists 1668 GR 64349 Potent, selective NK2 agonist 1 mg 325

1669 GR 73632 Potent, selective NK1 agonist 1 mg 305

1068 Senktide Tachykinin NK3 agonist 500 µg 125

Antagonists 1274 GR 159897 Non-peptide, potent NK2 antagonist 10 mg

50 mg

195

760

1145 L-733,060 Potent NK1 antagonist 10 mg

50 mg

195

760

1635 RP 67580 Potent and selective NK1 antagonist 10 mg

50 mg

195

760

4672 SB 223412 Potent, selective non-peptide NK3 antagonist; brain penetrant 10 mg

50 mg

180

705


GPCR ReSeaRCh

tocris.com | 11


Free Fatty Acid Receptors

O

SNH

O OO

CO2H

FO

HNS

O

O

GSK 137647 (5257)Potent and selective FFA4 (GPR120) agonist

TUG 891 (4601)Potent and selective FFA4

(GPR120) agonist

AH 7614 (5256)Selective FFA4 (GPR120) antagonist

Featured Free Fatty Acid Receptor Agonists and Antagonists

Class A11 Free Fatty Acid (FFA) Receptors

Agonists 5257 GSK 137647 Potent and selective FFa4 (GPR120) agonist 10 mg

50 mg

110

405

4601 TUG 891 Potent and selective FFa4 (GPR120) agonist 10 mg

50 mg

175

635

Antagonists 5256 ah 7614 Selective FFa4 (GPR120) antagonist 10 mg

50 mg

110

405

5357 DC 260126 FFa1 (GPR40) antagonist 10 mg

50 mg

85

310

Hydroxycarboxylic Acid (HCA) Receptors

Agonists 1762 acifran GPR109a (hCa2) and GPR109B agonist; hypolipidemic agent 10 mg

50 mg

145

560

4599 3,5-DhBa Selective hCa1 agonist 50 mg 65

4622 MK 1903 Potent and selective GPR109a (hCa2) agonist 10 mg

50 mg

195

760

Class A11/12 Purinergic (P2Y) Receptors

Agonists 3245 aTP P2 agonist 50 mg 80

3209 α,β-Methyleneadenosine 5ʹ-triphosphate trisodium salt

P2 agonist 10 mg 180

1624 2-Methylthioadenosine diphosphate Potent agonist for P2Y1, P2Y12 and P2Y13 10 mg 270

2157 MRS 2365 highly potent and selective P2Y1 agonist 1 mg 320

2915 MRS 2690 Potent P2Y14 agonist 1 mg 285

2502 MRS 2693 trisodium salt Selective P2Y6 agonist 1 mg 225

3884 MRS 2768 tetrasodium salt Selective P2Y2 agonist 1 mg 285

4261 MRS 4062 Selective P2Y4 agonist 1 mg 255

2715 PSB 0474 Potent and selective P2Y6 agonist 1 mg 285

4333 PSB 1114 Potent, selective P2Y2 agonist 1 mg 285

3280 2-ThioUTP tetrasodium salt Potent and selective P2Y2 agonist 1 mg 290

3279 UTPγS trisodium salt Selective P2Y2/4 agonist 1 mg 200

Antagonists 4890 aR-C 118925XX Selective, competitive P2Y2 antagonist 5 mg 275

3321 aR-C 66096 tetrasodium salt Potent and selective P2Y12 antagonist 1 mg 305

1820 (+)-Clopidogrel Selective P2Y12 antagonist 10 mg

50 mg

180

720

5316 elinogrel P2Y12 antagonist 10 mg

50 mg

195

775

0900 MRS 2179 tetrasodium salt Selective P2Y1 antagonist 10 mg

50 mg

210

820



12 |

2402 MRS 2211 Competitive P2Y13 antagonist 10 mg

50 mg

125

445

2158 MRS 2279 Selective, high affinity P2Y1 antagonist 1 mg 320

2159 MRS 2500 extremely potent and selective P2Y1 antagonist 1 mg 305

2146 MRS 2578 Selective P2Y6 antagonist 10 mg

50 mg

125

420

3830 NF 340 Selective P2Y11 antagonist 10 mg 195

3983 PSB 0739 highly potent P2Y12 antagonist 10 mg

50 mg

175

665

Class A12 Platelet-activating Factor (PAF) Receptor

Agonists 3022 edelfosine PaF receptor agonist 10 mg 125

2940 PaF (C16) endogenous PaF receptor agonist 1 mg 65

Antagonists 2339 WeB 2086 Potent PaF receptor antagonist 1 mg

10 mg

125

240

Class A13 Cannabinoid (CB) Receptors

Agonists 2928 CB 13 Potent dual CB1/CB2 agonist 10 mg

50 mg

140

490

2764 GP 1a highly selective CB2 agonist 10 mg

50 mg

215

865

3088 hU 308 Potent and selective CB2 agonist 10 mg

50 mg

245

980

Antagonists 1117 aM 251 Potent CB1 antagonist; also GPR55 agonist 1 mg

10 mg

50 mg

80

160

600

1115 aM 281 Potent, selective CB1 antagonist/inverse agonist 10 mg

50 mg

195

760

1120 aM 630 CB2 selective antagonist/inverse agonist 10 mg

50 mg

195

760

1570 (-)-Cannabidiol Natural cannabinoid; GPR55 antagonist, weak CB1 antagonist and CB2 inverse agonist

10 mg

50 mg

160

600

2479 JTe 907 Selective CB2 receptor antagonist/inverse agonist 10 mg

50 mg

195

760

4605 (±)-SLV 319 Potent and selective CB1 receptor antagonist 10 mg

50 mg

200

795

Modulators 5321 PSNCBaM-1 CB1 receptor negative allosteric modulator 10 mg

50 mg

180

705

Antagonists 0923 SR 141716a Selective CB1 receptor antagonist 10 mg

50 mg

110

405

Other 1445 N-arachidonylglycine endocannabinoid; suppresses pain in vivo 5 mg

25 mg

125

445

2540 Tocrifluor T1117 Novel fluorescent cannabinoid ligand; fluorescent form of aM 251 (Cat. No. 1117)

100 µg 255


GPCR ReSeaRCh

tocris.com | 13


Melanocortin MC4 Receptor Antagonist

ML 00253764 Cat. No. 4854

ML00253764isanon-peptideMC4receptorantagonist(IC50valuesare320,810and2120nMforMC4,MC3andMC5receptors,respectively).Thecompoundincreasesfoodintakeandreduceslossofleanbodymassintumorbearingmice.ML 00253764isalsobrainpenetrant.

JNJ 27141491 (Cat. No. 5176)

N

F

F NHS

OOMe

O N

ML 00253764 (4854)

Br

OMe

F

NHN

TC-G 1008 (5355)

BIBN 4096 (4561)

N

N

N

NH

NH

Cl

NH

SOO

NHN

N

HNO

O

HN

N N NO O

NH2

Br

Br

HO


N

N N

N

NH

O

N

O

CMPD101 (5642)

N

N N

NNH

O

HN

F3C

MA 2029 (4934)

F

N

O

NH

ONHO

HN

OH

Melanocortin (MC) Receptors

Agonists 3492 aCTh (1-39) Potent endogenous MC2 agonist 1 mg 320

4053 BMS 470539 Potent, selective MC1 receptor agonist 10 mg

50 mg

225

900

3013 [Nle4,D-Phe7]-α-MSh Melanocortin receptor agonist 1 mg 160

3032 ThIQ Potent and selective MC4 receptor agonist 1 mg 215

Antagonists 4854 ML 00253764 Melanocortin MC4 receptor antagonist; brain penetrant 10 mg

50 mg

210

820

4919 PG 106 Selective MC3 receptor antagonist 1 mg 245

Sphingosine-1-phosphate Receptors

Agonists 3601 CYM 5442 Selective S1P1 receptor agonist 10 mg

50 mg

200

795

5418 CYM 5520 Selective S1P2 allosteric agonist 10 mg

50 mg

160

600

4897 CYM 5541 Selective S1P3 receptor allosteric agonist 10 mg

50 mg

160

630

1370 Sphingosine-1-phosphate endogenous agonist at S1P1-5 1 mg 175

Antagonists 4679 CYM 50358 Potent and selective S1P4 antagonist 10 mg

50 mg

210

820

2392 JTe 013 S1P2 receptor antagonist 10 mg 195

5328 TY 52156 S1P3 receptor antagonist 10 mg

50 mg

160

630

4195 VPC 23019 S1P1 and S1P3 antagonist 10 mg 285

3602 W146 Potent and selective S1P1 receptor antagonist 1 mg 155

Class A13/15 Lysophosphatidic Acid (LPA) Receptors

Agonists 4779 GRI 977143 Selective LPa2 non-lipid agonist 10 mg

50 mg

180

720

Antagonists 4878 h2L5186303 Potent and selective LPa2 antagonist 10 mg

50 mg

180

720

5056 Ki 16425 LPa1 and LPa3 antagonist 10 mg

50 mg

165

635

4708 TC LPa5 4 LPa5 antagonist 10 mg

50 mg

195

760



14 |

Class A14 Prostanoid Receptors

Agonists 1620 alprostadil Prostaglandin; vasodilator and antiplatelet agent in vivo 10 mg

50 mg

165

635

4180 Beraprost sodium Potent prostacyclin IP receptor agonist 1 mg 110

2295 (±)-Cloprostenol sodium salt Water-soluble PGF2α analog and potent FP receptor agonist 10 mg 360

2038 Iloprost Prostacyclin (PGI2) analog 1 mg 285

2296 Prostaglandin e2 Major endogenous prostanoid 10 mg 145

4214 Prostaglandin F2α Naturally-occurring prostanoid; potent vasoconstrictor 10 mg 215

3351 Selexipag Selective prostacyclin IP1 receptor agonist 10 mg

50 mg

215

865

5349 Treprostinil Potent prostacyclin (PGI2) analog 10 mg 225

Antagonists 2514 L-161,982 Selective eP4 antagonist 10 mg 275

3342 L-798,106 Potent and highly selective eP3 antagonist 10 mg

50 mg

195

760

5406 ONO 8130 eP1 antagonist 10 mg

50 mg

225

900

3565 ONO ae3 208 high affinity and selective eP4 antagonist 10 mg

50 mg

190

740

4818 PF 04418948 Potent and selective eP2 antagonist 10 mg

50 mg

180

720

4268 Ro 1138452 Selective prostacyclin IP antagonist 10 mg

50 mg

190

740

5052 TG 4-155 high affinity and selective eP2 antagonist 10 mg

50 mg

195

760

Thromboxane (TP) Receptors

Agonists 1932 U 46619 Potent, stable thromboxane a2 (TP) receptor agonist 1 mg 145

Antagonists 5568 S 18886 Potent thromboxane a2 (TP) receptor antagonist 10 mg 130

Class A15 GPR35

Agonists 4298 Pamoic acid disodium salt GPR35 agonist 50 mg 100

Antagonists 4293 CID 2745687 GPR35 antagonist 10 mg

50 mg

175

665

4172 ML 145 GPR35 antagonist 10 mg

50 mg

190

740

Protease-activated Receptors (PARs)

Agonists 3015 2-Furoyl-LIGRLO-amide Potent and selective PaR2 agonist 1 mg 125

3010 SLIGKV-Nh2 PaR2 agonist 5 mg 145

1468 SLIGRL-Nh2 PaR2-activating peptide 1 mg 245

1464 TFLLR-Nh2 PaR1-activating peptide 1 mg 255

3497 TRaP-6 PaR1 peptide fragment (residues 42-47); acts as a PaR1 agonist

5 mg 195

Antagonists 4751 FSLLRY-Nh2 PaR2 peptide antagonist 1 mg 100

5387 ML 354 Selective PaR4 antagonist 10 mg

50 mg

140

505

1592 SCh 79797 Potent, selective non-peptide PaR1 antagonist 10 mg

50 mg

215

865

1488 tcY-Nh2 Selective PaR4 antagonist 1 mg 180


GPCR ReSeaRCh

tocris.com | 15


β2 Adrenergic Receptor in Complex with ICI 118,551 Crystal Structure of the β2 Adrenergic Receptor in Complex with the β2 Antagonist ICI 118,551

Image adapted from the RSCB PDB (www.rcsb.org) of PDB ID: 3NY8 Wacker et al (2010) J.Am.Chem.Soc. 132 11443. PMID 20669948.

• ICI118,551bindstotheorthostericbindingsiteofβ2

• ICI118,551isaselectiveβ2antagonistthatexhibitsselectivityforβ2overβ1andβ3receptors

• Thecompoundisactivein vivo

Cat. No. 0821

CXCR4 – IT1t

NN

S

SN

NH


NHHO

O

A2A – ZM 241385

OH

NH

N

N N

N

NO

NH2

D3 – Eticlopride

H1 – Doxepin

O

N

CRF1R – CP-376395

N

O NH

3212

4596 0508

0821

1036MGLUR1 – LY 341495

O

CO2HH2N

OHO

1209

1847

N NH

O HO

OCl

extracellularMembraneIntracellular

Class A17 α Adrenergic Receptors

Agonists 1052 a 61603 α1a agonist 10 mg

50 mg

175

635

0888 Cirazoline Selective α1 agonist 10 mg 140

2749 Dexmedetomidine Potent, highly selective α2 agonist; active isomer of medetomidine (Cat. No. 5160)

10 mg

50 mg

175

635

0475 Dihydroergotamine Partial α agonist; non-selective 100 mg 110

5169 Noradrenaline endogenous adrenergic hormone and neurotransmitter 50 mg 65

Antagonists 0986 Imiloxan highly selective α2B antagonist 10 mg

50 mg

140

470

β Adrenergic Receptors

Agonists 0948 BRL 37344, sodium salt β3 agonist 10 mg

50 mg

160

600

1499 CL 316243 highly selective β3 agonist 10 mg

50 mg

180

705

0515 Dobutamine β1 and β2 agonist 50 mg 190

1448 Formoterol Potent and selective β2 agonist 10 mg

50 mg

145

545

1747 Isoproterenol Standard selective β agonist 100 mg 100

2197 L-755,507 Very potent and selective β3 partial agonist 10 mg

50 mg

175

665

0634 Salbutamol Non-selective β-adrenergic agonist 250 mg 140

0950 Xamoterol β1 selective partial agonist 10 mg

50 mg

160

600

Antagonists 0906 Betaxolol Selective β1 antagonist 10 mg

50 mg

145

545

2685 Carvedilol β-adrenoceptor and α1-adrenoceptor antagonist 50 mg 100

1024 CGP 20712 highly potent and selective β1 antagonist 10 mg

50 mg

195

760

0993 Cyanopindolol β-adrenergic receptor antagonist; also 5-hT1a/1B antagonist 10 mg

50 mg

145

560

0821 ICI 118,551 Very selective β2 antagonist 10 mg

50 mg

175

635



16 |

D3 Dopamine Receptor in Complex with EticloprideCrystal Structure of the D3 Dopamine Receptor in Complex with the D3/D2 Antagonist Eticlopride

Image adapted from the RSCB PDB (www.rcsb.org) of PDB ID: 3PBL Chien et al (2010) Science 330 1091. PMID 21097933.

• EticlopridebindstopartoftheD3bindingpocketdefinedbysidechainsofhelicesIII,V,VIandVII.

• EticloprideisaselectiveD3/D2receptorantagonist(Kivaluesare160and500nM,respectively)

• Thecompoundisanantipsychotic

Cat. No. 1847

CXCR4 – IT1t

NN

S

SN

NH


NHHO

O

A2A – ZM 241385

OH

NH

N

N N

N

NO

NH2

D3 – Eticlopride

H1 – Doxepin

O

N

CRF1R – CP-376395

N

O NH

3212

4596 0508

0821

1036MGLUR1 – LY 341495

O

CO2HH2N

OHO

1209

1847

N NH

O HO

OCl

extracellular

Membrane

Intracellular

2760 L-748,337 Selective β3 antagonist 10 mg

50 mg

175

665

1511 SR 59230a Potent and selective β3 antagonist 10 mg

50 mg

180

720

0649 (S)-Timolol β1 antagonist 100 mg 100

Dopamine D1/D5 Receptors

Agonists 1701 a 77636 Potent, selective D1-like agonist; orally active 10 mg

50 mg

195

760

0884 Dihydrexidine Selective D1-like agonist 5 mg

25 mg

145

560

0922 SKF 38393 Selective D1-like agonist 100 mg 145

1447 SKF 81297 D1 agonist 10 mg

50 mg

195

760

2074 SKF 83959 D1-like partial agonist 10 mg

50 mg

180

695

Antagonists 0925 SCh 23390 Standard selective D1-like antagonist; also 5-hT2C and 5-hT1C agonist

10 mg

50 mg

145

545

2299 SCh 39166 high affinity D1/D5 antagonist 10 mg

50 mg

195

760

1586 SKF 83566 Potent, selective D1-like antagonist 10 mg

50 mg

110

385

Dopamine D2/D3/D4 Receptors

Agonists 4552 a 412997 Selective D4 agonist 10 mg

50 mg

145

520

1243 (+)-PD 128907 D3 agonist (D3 ≥ D2 > D4) 10 mg

50 mg

245

980

1065 PD 168077 high affinity, selective D4 agonist 10 mg

50 mg

160

600

2773 Sumanirole D2-selective agonist 10 mg

50 mg

190

740

Antagonists 1847 eticlopride Selective D2/D3 antagonist 10 mg

50 mg

145

545

1003 L-741,626 high affinity D2 antagonist 10 mg

50 mg

140

500


GPCR ReSeaRCh

tocris.com | 17


H1 Histamine Receptor in Complex with DoxepinCrystal Structure of the H1 Histamine Receptor in Complex with the H1 Antagonist Doxepin

Image adapted from the RSCB PDB (www.rcsb.org) of PDB ID: 3RZe Shimamura et al (2011) Nature 475 65. PMID 21697825.

• DoxepinbindsdeepintheH1bindingpocketdefinedbysidechainsofhelicesIII,VandVI,andinteractswiththeTrp4286.48residue

• DoxepinisahighaffinityH1receptorantagonist(Kd=310pM)

• Thecompoundisatricyclicantidepressant

Cat. No. 0508

CXCR4 – IT1t

NN

S

SN

NH


NHHO

O

A2A – ZM 241385

OH

NH

N

N N

N

NO

NH2

D3 – Eticlopride

H1 – Doxepin

O

N

CRF1R – CP-376395

N

O NH

3212

4596 0508

0821

1036MGLUR1 – LY 341495

O

CO2HH2N

OHO

1209

1847

N NH

O HO

OCl


1004 L-741,742 highly selective D4 antagonist 10 mg

50 mg

145

530

1002 L-745,870 highly selective D4 antagonist 10 mg

50 mg

145

530

4207 SB 277011a Selective D3 antagonist 10 mg

50 mg

175

635

Dopamine Receptors (Non-selective)

Agonists 2073 (R)-(-)-apomorphine Dopamine agonist; non-subtype-selective 50 mg 100

Antagonists 1847 eticlopride Selective D2/D3 antagonist 10 mg

50 mg

145

545

Trace Amine 1 Receptor (TA1)

Agonists 5252 Ractopamine Ta1 agonist 50 mg 55

Antagonists 4518 ePPTB Ta1 antagonist/inverse agonist 10 mg

50 mg

145

560

Class A17/18 Histamine Receptors

Agonists 0646 hTMT h1 / h2 agonist 10 mg

50 mg

145

545

0569 (R)-(-)-α-Methylhistamine Potent, standard h3 agonist 10 mg

50 mg

140

505

2342 4-Methylhistamine Selective, high affinity h4 agonist 10 mg

50 mg

180

720

2478 2-Pyridylethylamine h1 receptor agonist 50 mg 85

Antagonists 3489 astemizole Orally active, potent h1 antagonist; also KV11.1 (heRG) channel blocker

50 mg 80

3743 BF 2649 h3 receptor inverse agonist/antagonist 10 mg

50 mg

145

560

0508 Doxepin highly potent h1 antagonist; also binds to h4 receptor 1 g 80

4021 JNJ 7777120 Selective h4 receptor antagonist 10 mg

50 mg

160

600

0660 Mepyramine Selective h1 inverse agonist 100 mg 80

1070 Zolantidine Potent, centrally active h2 antagonist 10 mg

50 mg

160

600



18 |

Class A17/19 5-HT1 Receptors

Agonists 1317 CP 94253 Potent, selective 5-hT1B agonist 10 mg

50 mg

180

665

0529 8-hydroxy-DPaT Selective 5-hT1a agonist; also has moderate affinity for 5-hT7

10 mg

50 mg

80

240

3079 LY 334370 Selective 5-hT1F agonist 10 mg

50 mg

195

760

1985 PNU 142633 highly selective 5-hT1D agonist 10 mg 215

Antagonists 1477 GR 127935 Potent, selective 5-hT1B/1D antagonist 10 mg

50 mg

215

865

1054 GR 55562 5-hT1B antagonist 10 mg

50 mg

175

635

1242 SB 216641 Selective h5-hT1B antagonist 10 mg

50 mg

200

795

1221 SB 224289 Selective 5-hT1B antagonist 10 mg

50 mg

180

720

1253 (S)-WaY 100135 Potent, selective 5-hT1a antagonist 10 mg

50 mg

160

600

4380 WaY 100635 Potent, 5-hT1a silent antagonist; also D4 agonist 10 mg

50 mg

165

635

5-HT2 Receptors

Agonists 1059 BW 723C86 5-hT2B agonist 10 mg

50 mg

145

545

5171 NBOh-2C-CN high affinity, selective 5-hT2a agonist 10 mg

50 mg

210

820

1854 Ro 60-0175 Potent, selective 5-hT2C agonist 10 mg

50 mg

145

560

2592 TCB-2 Potent, high affinity 5-hT2a agonist 10 mg

50 mg

195

760

Antagonists 4173 MDL 100907 Potent and selective 5-hT2a antagonist 10 mg

50 mg

240

935

1644 Mesulergine 5-hT2a and 5-hT2C antagonist; also dopamine receptor partial agonist

10 mg

50 mg

180

705

1955 Ritanserin Potent 5-hT2 antagonist 10 mg

50 mg

80

240

2993 RS 127445 Selective, high affinity 5-hT2B antagonist 10 mg

50 mg

180

720

1661 SB 206553 Potent, selective 5-hT2C/5-hT2B antagonist; orally active 10 mg

50 mg

200

795

1374 SB 215505 5-hT2B/2C antagonist 10 mg

50 mg

180

720

2901 SB 242084 Selective 5-hT2C antagonist; brain penetrant 10 mg

50 mg

195

760

5-HT3 Receptors

Agonists 0558 2-Methyl-5-hydroxytryptamine 5-hT3 agonist; also potent 5-hT6 ligand 10 mg

50 mg

100

355

Antagonists 1795 Zacopride highly potent 5-hT3 receptor antagonist; also 5-hT4 agonist 10 mg

50 mg

145

530

5-HT4 Receptors

Agonists 4374 BIMU 8 Potent 5-hT4 receptor full agonist 10 mg

50 mg

180

705

Antagonists 1322 GR 113808 Potent, selective 5-hT4 antagonist 10 mg

50 mg

175

665

1658 GR 125487 Potent, selective 5-hT4 antagonist; active in vivo 10 mg

50 mg

180

720


GPCR ReSeaRCh

tocris.com | 19


5-ht5 Receptors

Antagonists 3188 SB 699551 Selective 5-ht5a antagonist 10 mg

50 mg

195

760

5-HT6 Receptors

Agonists 4337 ST 1936 Selective, high affinity 5-hT6 agonist 10 mg

50 mg

175

665

3904 WaY 208466 Selective 5-hT6 agonist 10 mg 190

Antagonists 1961 SB 258585 Potent, selective 5-hT6 antagonist 10 mg

50 mg

165

635

3189 SB 399885 Potent and selective 5-hT6 antagonist 10 mg

50 mg

195

760

5-HT7 Receptors

Agonists 1968 aS 19 Potent 5-hT7 agonist 10 mg

50 mg

180

720

Antagonists 1612 SB 269970 Potent and selective 5-hT7 antagonist; brain penetrant 10 mg

50 mg

195

760

5-HT Receptors (Non-selective)

Agonists 3547 Serotonin endogenous 5-hT receptor agonist 50 mg 80

Antagonists 0996 Cyproheptadine Non-selective 5-hT2 antagonist 50 mg 100

1064 Methysergide 5-hT1/5-hT2 antagonist 10 mg

50 mg

195

760

Class A18 Adenosine A1 Receptors

Agonists 1705 2-Chloro-N6-cyclopentyladenosine Potent, selective a1 agonist 10 mg

50 mg

145

530

3576 (±)-5ʹ-Chloro-5ʹ-deoxy-eNBa highly selective a1 agonist 10 mg

50 mg

195

760

5122 Dansyl-NeCa Potent and selective fluorescent a1 agonist 1 mg 200

Antagonists 0439 DPCPX a1 selective antagonist 100 mg 175

Adenosine A2A Receptors

Agonists 1063 CGS 21680 a2a agonist 10 mg

50 mg

255

1015

4334 PSB 0777 Potent adenosine a2a agonist 10 mg

50 mg

210

820

Antagonists 5147 Istradefylline Potent and selective adenosine a2a antagonist 10 mg

50 mg

160

600

2463 SCh 442416 Very selective, high affinity a2a antagonist 1 mg

10 mg

50 mg

100

195

760

2270 SCh 58261 Potent, highly selective a2a antagonist 10 mg

50 mg

180

720

1036 ZM 241385 Potent, highly selective a2a antagonist 10 mg

50 mg

160

600

Adenosine A2B Receptors

Agonists 4472 BaY 60-6583 Potent a2B agonist; cardioprotective 10 mg

50 mg

180

705

Antagonists 2752 MRS 1754 Selective a2B antagonist 10 mg

50 mg

195

760

2009 PSB 1115 Selective human a2B antagonist; water-soluble 10 mg

50 mg

145

560

3198 PSB 603 highly selective a2B antagonist 10 mg

50 mg

180

695



20 |

Adenosine A2A Receptor in Complex with ZM 241385Crystal Structure of the Adenosine A2A Receptor in Complex with the A2A Antagonist ZM 241385

Image adapted from the RSCB PDB (www.rcsb.org) of PDB ID: 3eML Jaakola et al (2008) Science 322 1211. PMID 18832607.

• ZM241385bindsintheA2AbindingpocketlocatedclosetohelicesVIandVII,andinteractswiththeTRP2466.48residue

• ZM241385isapotentandselectiveA2AreceptorantagonistthatexhibitsselectivityforA2AoverA1,A2BandA3receptors

• Thecompoundisactivein vivo

Cat. No. 1036

CXCR4 – IT1t

NN

S

SN

NH


NHHO

O

A2A – ZM 241385

OH

NH

N

N N

N

NO

NH2

D3 – Eticlopride

H1 – Doxepin

O

N

CRF1R – CP-376395

N

O NH

3212

4596 0508

0821

1036MGLUR1 – LY 341495

O

CO2HH2N

OHO

1209

1847

N NH

O HO

OCl


Adenosine A3 Receptors

Agonists 1104 2-Cl-IB-MeCa highly selective a3 agonist 10 mg

50 mg

325

1305

1579 heMaDO high affinity and selective a3 agonist 10 mg

50 mg

195

760

1066 IB-MeCa a3 selective agonist 5 mg

25 mg

195

760

5428 MRS 5698 high affinity and selective a3 agonist 1 mg 320

Adenosine Receptors (Non-selective)

Agonists 3624 adenosine endogenous adenosine receptor agonist 50 mg 65

1691 NeCa high affinity adenosine receptor agonist 10 mg

50 mg

70

195

Antagonists 3200 XaC adenosine receptor antagonist 10 mg

50 mg

140

505

Acetylcholine Muscarinic Receptors

Agonists 1067 Oxotremorine M Muscarinic receptor agonist 100 mg 125

3569 Xanomeline Functionally selective M1 agonist 10 mg

50 mg

165

635

Antagonists 1105 aF-DX 116 Selective M2 antagonist 10 mg

50 mg

155

590

1425 (S)-(+)-Dimethindene M2-selective antagonist 10 mg

50 mg

160

600

2507 J 104129 Potent, selective M3 antagonist 10 mg 180

1671 PD 102807 Selective M4 antagonist 10 mg

50 mg

195

760

3727 VU 0255035 highly selective M1 antagonist 10 mg

50 mg

175

665

1414 Scopolamine Non-selective muscarinic antagonist 1 g 80

Modulators 3634 VU 0238429 Selective positive allosteric modulator of M5 receptors 10 mg

50 mg

145

560

3383 VU 152100 Positive allosteric modulator of M4 receptors 10 mg

50 mg

165

635


GPCR ReSeaRCh

tocris.com | 21

DREADD LigandsDesigner receptors exclusively activated by designer drugs (DREADDs) are genetically modified GPCRs that are activated by physiologically inert ligands. DREADDs enable the precise experimental manipulation of neuronal signaling, and have multiple non-invasive in vivo applications.

Three new DREADD ligands have recently been added to the Tocris range:

Cat. No. Product name Description

4936 Clozapine N-oxide activator of muscarinic DReaDDs

5548 DREADD agonist 21 NEW Potent muscarinic hM3Dq DReaDD agonist

5549 Perlapine NEW Potent and selective hM3Dq DReaDD agonist

5611 Salvinorin B NEW activates the κ-opioid DReaDD (KORD)

For more information please visit www.tocris.com/DREADDs

Other GPCRs GPBA receptors (TGR5)

Agonists 4478 GPBaR-a GPBa receptor agonist 10 mg

50 mg

210

820

5129 TC-G 1005 Potent and selective GPBa receptor agonist 10 mg

50 mg

195

775

Neuropeptide FF/AF (NPFF) Receptors

Agonists 3137 Neuropeptide FF endogenous NPFF1 and NPFF2 agonist 1 mg 140

5677 RFRP-1 (human) Potent NPFF receptor agonist 1 mg 160

Antagonists 2707 BIBP 3226 Mixed NPFF and NPY Y1 receptor antagonist 1 mg

10 mg

140

270

Orphan GPCRs

Agonists 4177 aS 1269574 GPR119 receptor agonist 10 mg

50 mg

175

665

5666 JNJ 63533054 Potent and selective GPR139 agonist 10 mg

50 mg

145

560

1484 Oleylethanolamide endogenous GPR119 agonist; also GPR55 agonist 10 mg

50 mg

100

345

4074 PF9 Potent GPR17 agonist 1 mg 245

5151 Prosaptide TX14(a) Potent GPR37 and GPR37L1 agonist 1 mg 160

5355 TC-G 1008 Potent and selective GPR39 agonist 10 mg

50 mg

190

740

4255 TC-O 9311 Potent and selective GPR139 agonist 10 mg

50 mg

175

665

Antagonists 5203 NIBR 189 Potent and selective eBI2 (GPR183) receptor antagonist 10 mg

50 mg

165

635

Sensory Neuron-specific Receptor

Agonists 1763 BaM (8-22) Selective agonist for the sensory-neuron specific receptor (SNSR)

1 mg 310



22 |

Potent and Selective CGRP Receptor Antagonist

BIBN 4096 Cat. No. 4561

BIBN4096isapotentandselectiveCGRPreceptorantagonist(IC50valuesare0.03and6.4nMforhumanandratCGRPreceptors,respectively).ThecompounddisplayshighaffinityforhumanCGRPreceptors(Ki=14.4pM),andnosignificantaffinityfor75otherreceptors.

JNJ 27141491 (Cat. No. 5176)

N

F

F NHS

OOMe

O N

ML 00253764 (4854)

Br

OMe

F

NHN

TC-G 1008 (5355)

BIBN 4096 (4561)

N

N

N

NH

NH

Cl

NH

SOO

NHN

N

HNO

O

HN

N N NO O

NH2

Br

Br

HO


N

N N

N

NH

O

N

O

CMPD101 (5642)

N

N N

NNH

O

HN

F3C

MA 2029 (4934)

F

N

O

NH

ONHO

HN

OH

Class B: Secretin-likeThe Secretin-like receptor class consists of receptors for neuropeptides and peptide hormones, including glucagon, secretin and calcitonin receptors. The receptors are key drug targets for the study of many human diseases including, diabetes, neurodegeneration, cardiovascular disease, psychiatric disorders and cancer.

Calcitonin and Related Receptors

Agonists 3012 α-CGRP (human) CGRP receptor agonist 1 mg 385

1161 CGRP (rat) CGRP receptor agonist; potent vasodilator 100 µg 140

5031 Pramlintide Synthetic version of amylin (Cat. No. 3418) 500 µg 215

Antagonists 3419 aC 187 Potent and selective amylin receptor antagonist 500 µg 285

4561 BIBN 4096 Potent and selective CGRP receptor antagonist 10 mg 275

1169 CGRP 8-37 (rat) CGRP1 receptor antagonist 500 µg 285

Corticotropin-releasing factor (CRF) Receptors

Agonists 1151 CRF (human, rat) Stimulates aCTh release 200 µg 160

Antagonists 2778 antalarmin CRF1 antagonist 10 mg

50 mg

195

760

2071 antisauvagine-30 Potent, selective and competitive CRF2 antagonist 1 mg 370

2391 astressin 2B Selective CRF2 antagonist 500 µg 370

2779 CP 154526 Selective, non-peptide CRF1 antagonist 10 mg

50 mg

195

760

3212 CP 376395 Potent and selective CRF1 antagonist 10 mg

50 mg

180

720

2070 K 41498 highly selective and potent CRF2 antagonist 1 mg 370

3100 NBI 35965 Potent and selective CRF1 antagonist 10 mg

50 mg

195

780

Gastric Inhibitory Polypeptide (GIP) Receptor

Agonists 2257 GIP (1-39) highly potent insulinotropic peptide 1 mg 325

2084 GIP (human) Potent insulinotropic gut hormone 1 mg 370

Glucagon Receptor

Antagonists 2216 des-his1-[Glu9]-Glucagon (1-29) Glucagon receptor antagonist 1 mg 275

2311 L-168,049 Potent, human glucagon receptor antagonist; orally active 10 mg

50 mg

160

600

Other 2094 Oxyntomodulin endogenous gut peptide; modulates feeding and metabolism 1 mg 305


GPCR ReSeaRCh

tocris.com | 23

CRF1 Receptor in Complex with CP 376395Crystal Structure of the CRF1 Receptor in Complex with the CRF1 Antagonist CP 376395

Image adapted from the RSCB PDB (www.rcsb.org) of PDB ID: 4K5Y hollenstein et al (2013) Nature 499 438. PMID 23863939.

• CP376395bindstoahydrophobicpocket,definedbyresiduesofTM3,TM5andTM6,locatedinthecytoplasmicdomainofthereceptor

• CP376395isanon-peptidehighaffinityandselectiveCRF1antagonist(Kivaluesare12and>10,000nMforCRF1andCRF2receptors,respectively)

• ThecompoundattenuatesCRF-inducedHPAaxisactivationin vivo

Cat. No. 3212

CXCR4 – IT1t

NN

S

SN

NH


NHHO

O

A2A – ZM 241385

OH

NH

N

N N

N

NO

NH2

D3 – Eticlopride

H1 – Doxepin

O

N

CRF1R – CP-376395

N

O NH

3212

4596 0508

0821

1036MGLUR1 – LY 341495

O

CO2HH2N

OHO

1209

1847

N NH

O HO

OCl


Glucagon-like Peptide Receptors

Agonists 1933 exendin-4 Potent GLP-1 receptor agonist 1 mg 325

5374 GLP-1 (7-37) endogenous bioactive GLP-1 receptor ligand 1 mg 370

2258 GLP-2 (human) endogenous hormone; displays intestinotrophic activity 1 mg 255

2259 GLP-2 (rat) endogenous hormone; displays intestinotrophic activity 1 mg 255

2082 Glucagon-like peptide 1 (7-36) (human, rat)

Potent insulinotropic peptide 1 mg 370

Antagonists 2081 exendin-3 (9-39) Potent GLP-1 receptor antagonist 1 mg 370

3266 GLP-1 (9-36) Metabolite of GLP-1-(7-36) (Cat. No. 2082) 1 mg 285

Modulators 4778 BeTP Positive allosteric modulator of GLP-1 receptors 10 mg

50 mg

175

680

PACAP Receptors

Agonists 1183 PaCaP 1-27 Potent stimulator of adenylyl cyclase 100 µg 145

1186 PaCaP 1-38 Potent stimulator of adenylyl cyclase 100 µg 180

Antagonists 3236 PaCaP 6-38 Potent PaC1 receptor antagonist 100 µg 145

Parathyroid Hormone (PTH) Receptors

Agonists 5487 DPC aJ1951 Potent PTh receptor agonist 1 mg 180

3011 Parathyroid hormone (1-34) (human)

PTh receptor agonist 1 mg 290

Secretin Receptor

Agonists 1918 Secretin (human) Gastrointestinal peptide 1 mg 200

1919 Secretin (rat) Gastrointestinal peptide 1 mg 200

VIP Receptors

Agonists 2711 Bay 55-9837 Potent and selective VPaC2 agonist 1 mg 310

1911 VIP (human, rat, mouse, rabbit, canine, porcine)

endogenous VIP receptor agonist 1 mg 175

Antagonists 3054 [D-p-Cl-Phe6,Leu17]-VIP Selective VIP receptor antagonist 1 mg 255

1905 VIP (6-28) (human, rat, porcine, bovine)

VIP receptor antagonist 1 mg 245



24 |

Class C: GlutamateThe Glutamate receptor class of GPCRs consists of receptors that have amino acids, ions and sugars as their endogenous ligands, including glutamate, GABA and calcium. Class C receptors are highly susceptible to modulation by ligands that bind to allosteric binding sites, particularly metabotropic glutamate receptors.

Calcium-sensing Receptor

Agonists 4749 Strontium chloride Calcium sensing receptor (CaSR) agonist 50 mg 55

Antagonists 3626 NPS 2143 Selective antagonist of the calcium-sensing receptor; orally active calcilytic agent

10 mg

50 mg

180

720

Modulators 4387 Calhex 231 Negative allosteric modulator of the calcium-sensing receptor

10 mg

50 mg

215

865

3815 R 568 Positive allosteric modulator of the human calcium-sensing receptor

10 mg

50 mg

155

590

GABAB Receptor

Agonists 0796 (R)-Baclofen Selective GaBaB agonist; active enantiomer of (RS)-Baclofen (Cat. No. 0417)

10 mg

50 mg

100

325

3400 RuBi-GaBa Caged GaBa; excitable by visible wavelength 10 mg 195

Antagonists 1245 CGP 35348 Brain penetrant, selective GaBaB antagonist 10 mg

50 mg

180

720

1246 CGP 52432 Potent, selective GaBaB antagonist 10 mg

50 mg

195

760


50 mg

195

760


50 mg

195

775

0984 SCh 50911 Selective, competitive, orally active GaBaB antagonist 10 mg

50 mg

210

820

Modulators 1513 CGP 7930 Positive modulator at GaBaB receptors 10 mg

50 mg

145

520

Glutamate (Metabotropic) Group I Receptors

Agonists 0187 (±)-trans-aCPD Group I/group II mGlu agonist 10 mg

50 mg

180

705

1049 ChPG mGlu5 selective agonist 10 mg

50 mg

125

430

3695 ChPG Sodium salt Selective mGlu5 agonist; sodium salt of ChPG (Cat. No. 1049)

10 mg

50 mg

130

465

0342 (RS)-3,5-DhPG Selective group I mGlu agonist 1 mg

10 mg

50 mg

80

145

545

0805 (S)-3,5-DhPG Selective group I mGlu agonist; active enantiomer of 3,5-DhPG (Cat. No. 0342)

5 mg

10 mg

145

255

0188 L-Quisqualic acid Group I mGlu agonist; also aMPa receptor agonist 1 mg

10 mg

50 mg

95

180

720

Antagonists 5614 aZD 2066 mGlu5 antagonist; orally bioavailable and brain penetrant 10 mg 180

2501 Bay 36-7620 Non-competitive mGlu1 antagonist with inverse agonist activity

10 mg 215

0323 (S)-4-Carboxyphenylglycine Competitive group I mGlu antagonist/weak group II agonist 10 mg

50 mg

255

1015

1028 CPCCOet Selective non-competitive mGlu1 receptor antagonist 10 mg

50 mg

145

560

2333 JNJ 16259685 highly potent, mGlu1-selective non-competitive antagonist

10 mg

50 mg

215

865

1237 LY 367385 Selective mGlu1a antagonist 10 mg

50 mg

175

665


GPCR ReSeaRCh

tocris.com | 25

Glutamate (Metabotropic) Receptors

NMe

NN

HN

O

CN

F

O

HN

O

N

N

S

N

N

Cl O

O

Cl

NH

O N

Cl

MPEP (1212)mGlu5 antagonist and positive allosteric

modulator at mGlu4

CDPPB (3235)Positive allosteric modulator at mGlu5

VU 0409106 (5322)Potent and selective negative allosteric

modulator at mGlu5

VU 0483605 (5377)Positive allosteric modulator at mGlu1

LY 487379 (3283)Positive allosteric modulator selective for mGlu2

O

OMe N

NSO O

F3C

Glutamate (Metabotropic) Receptor Allosteric Modulators

3696 (RS)-MCPG disodium salt Sodium salt of (RS)-MCPG (Cat. No. 0336) 10 mg

50 mg

145

560

1212 MPeP mGlu5 antagonist and positive allosteric modulator at mGlu4

10 mg

50 mg

145

520

2921 MTeP Potent, selective mGlu5 antagonist 10 mg

50 mg

160

600

Modulators 3235 CDPPB Positive allosteric modulator at mGlu5 10 mg

50 mg

165

635

5275 LSN 2463359 Potent and selective positive allosteric modulator at mGlu5

10 mg

50 mg

165

635

5322 VU 0409106 Potent and selective negative allosteric modulator at mGlu5

10 mg

50 mg

145

560

5377 VU 0483605 Positive allosteric modulator at mGlu1 10 mg

50 mg

145

560

Glutamate (Metabotropic) Group II Receptors

Agonists 0975 DCG IV Very potent, selective group II mGlu agonist; also NMDa agonist

1 mg

10 mg

50 mg

195

405

1660

3246 LY 354740 Potent and highly selective group II mGlu agonist 10 mg

50 mg

195

760

2453 LY 379268 highly selective group II mGlu agonist 10 mg

50 mg

325

1325

5064 LY 379268 disodium salt Selective group II mGlu receptor agonist; sodium salt of LY 379268 (Cat. No. 2453)

10 mg

50 mg

340

1360

Antagonists 1209 LY 341495 highly potent, selective group II antagonist 1 mg

10 mg

50 mg

100

225

965

4062 LY 341495 disodium salt Disodium salt of LY 341495 (Cat. No. 1209) 1 mg

10 mg

50 mg

125

240

935

0337 (S)-MCPG Non-selective mGlu antagonist; active isomer of (RS)-MCPG (Cat. No. 0336)

10 mg

50 mg

245

980

Modulators 3283 LY 487379 Positive allosteric modulator selective for mGlu2 10 mg

50 mg

160

600



26 |

mGlu1 Receptor in Complex with LY 341495Crystal Structure of the mGlu1 Receptor in Complex with the Group II mGlu Receptor Antagonist LY 341495

Image adapted from the RSCB PDB (www.rcsb.org) of PDB ID: 3KS9 Dobrovetsky et al (2009) Data yet to be published.

• DataregardingthebindingofLY341495tomGlu1haveyettobepublished

• LY341495isapotentandselectivegroupIImGlureceptorantagonist(IC50valuesare1.3and2.3nMformGlu3andmGlu2receptors,respectively)thatexhibitsselectivityovergroupIandIIImGlureceptors

• Thecompoundisbrainpenetrantandactivein vivo

Cat. No. 1209

CXCR4 – IT1t

NN

S

SN

NH


NHHO

O

A2A – ZM 241385

OH

NH

N

N N

N

NO

NH2

D3 – Eticlopride

H1 – Doxepin

O

N

CRF1R – CP-376395

N

O NH

3212

4596 0508

0821

1036MGLUR1 – LY 341495

O

CO2HH2N

OHO

1209

1847

N NH

O HO

OCl

Glutamate (Metabotropic) Group III Receptors

Agonists 2385 aMN 082 The first selective mGlu7 agonist 10 mg

50 mg

125

445

0103 L-aP4 Selective group III mGlu agonist 1 mg

10 mg

50 mg

95

180

705

Antagonists 0972 CPPG Very potent group III mGlu antagonist 10 mg

50 mg

165

635

2963 MMPIP Potent, allosteric mGlu7-selective antagonist 1 mg

10 mg

50 mg

85

165

635


GPCR ReSeaRCh

tocris.com | 27

GPCR allosteryGPCR allostery refers to the binding of ligands at sites on the receptor distinct from the orthosteric binding site, termed allosteric binding sites. Allosteric ligands can have intrinsic agonist/inverse agonist activity of their own, potentiate/decrease the effects of orthosteric ligands, or be neutral ligands with no intrinsic/modulatory activity.

Allosteric Modulation:

allosteric modulators are ligands that bind to receptor allosteric binding sites and influence the binding affinity and/or the signaling efficacy of the orthosteric ligand.

Those that potentiate the action of an orthosteric ligand are termed positive allosteric modulators (PaMs), whereas those that decrease the action are termed negative allosteric modulators (NaMs).

Unlike some allosteric ligands that have intrinsic agonist activity, allosteric modulators only have an effect in the presence of an orthosteric ligand (a ligand that binds to the binding site of the receptors endogenous ligand). They therefore have the advantage of being able to selectively influence physiological processes in tissues where the endogenous ligand is present.

allosteric modulators have been developed for Class a, B and C GPCRs. They are especially useful for Class B GPCRs, which have orthosteric binding sites that are difficult to target pharmacologically.

Key Characteristics of GPCR Allostery:

Enhanced Selectivity:allosteric binding sites have greater sequence divergence than the often conserved orthosteric site between receptor subtypes. Therefore allosteric ligands have the potential to offer greater subtype selectivity for receptors, such as the acetylcholine musarinic receptor.

The Saturation Effect:The effect of an allosteric ligand reaches a saturation point over a certain concentration, whereby no further pharmacological effects are observed. This enables greater fine-tuning of physiological responses, and lowers the risk of target-based overdose.

Probe Dependence:The effect of an allosteric modulator can be dependent on the orthosteric ligand. For example the adenosine a1 receptor allosteric modulator PD 81723 (Cat. No. 1363) enhances the affinity of the agonist [3h]Cha, but not the antagonist [3h]CPX, for the a1 receptor.

Biased Signaling:Biased agonism/modulation refers to the ability of allosteric (and orthosteric) ligands to preferentialy induce certain intracellular signaling pathways at the exclusion of others. allosteric modulators can also impose bias signaling on certain orthosteric agonists. See pg 30 for more information.

For references and further reading please see pg 31

Allosteric Modulation SchematicSchematic representing orthosteric and allosteric GPCR signaling. Positive allosteric modulators (PaMs) potentiate the binding affinity (dark green pointed arrow) and/or signaling efficacy (light red pointed arrow) of the orthosteric ligand, whereas negative allosteric modulators (NaMs) decrease the binding affinity (dark green flat arrow) and/or the signaling efficacy (light red flat arrow) of the orthosteric ligand. Neutral allosteric ligands have no intrinsic activity and have no effect on orthosteric signaling, although they are able to block the binding of other allosteric ligands to the allosteric binding site that they occupy. allosteric modulators exert their effects on orthosteric ligand-induced signaling by stabilizing the receptor in a conformation that is either favorable (PaMs) or unfavorable (NaMs) towards the ligands binding affinity and/or signaling efficacy. Figure adapted from Wooten et al (2013) Nat.Rev.Drug Discov. 12 630.

Orthosteric Signaling Positive Allosteric Modulation Negative Allosteric Modulation Neutral Allosteric Ligand

Signaling Potentiated signaling Reduced signaling Unaltered signaling

Neutral allosteric ligand

Orthosteric agonist

G protein

PAM NAM


28 |

Class F: FrizzledThe Frizzled receptor class of GPCRs consists of frizzled (FZD) receptors, FZD1-8 and the smoothened receptor (SMOH), and taste receptors. FZD1-8 are activated by Wnt proteins, whereas SMOH is activated by Hedgehog (Hh) signaling. The SMOH receptor is unique in that it does not directly interact with its endogenous ligand.

Smoothened Receptor Agonist

Purmorphamine Cat. No. 4551

Purmorphamineisasmoothenedreceptoragonistthatinducesosteogenesisinmousemesenchymalprogenitorcells.Thecompoundalsotransdifferentiatespre-adipocytesandmyoblastsintoosteoblastsincombinationwithBMP-4.

JNJ 27141491 (Cat. No. 5176)

N

F

F NHS

OOMe

O N

ML 00253764 (4854)

Br

OMe

F

NHN

TC-G 1008 (5355)

BIBN 4096 (4561)

N

N

N

NH

NH

Cl

NH

SOO

NHN

N

HNO

O

HN

N N NO O

NH2

Br

Br

HO


N

N N

N

NH

O

N

O

CMPD101 (5642)

N

N N

NNH

O

HN

F3C

MA 2029 (4934)

F

N

O

NH

ONHO

HN

OH

Licensing at TocrisTocris Bioscience has a long tradition of working with scientists to bring new discoveries out of the laboratory and into the commercial arena. We work in partnership with many scientists within both Universities and pharmaceutical companies to bring life science tools to the global research community.

The Tocris policy has always been to never knowingly infringe third party intellectual property. It is our intention to remain a responsible and ethical supplier, and work with the scientific community.

Our ExpertiseOur licensing department has significant experience of drafting contracts and has successfully executed licenses with a multitude of licensors, including:

• Large pharmaceutical companies• Start-up/spin-out companies • University technology transfer offices• Individual researchers

Contact UsTo discuss licensing opportunities, please contact our licensing team at [email protected]

Smoothened Receptor

Agonists 4551 Purmorphamine Smo receptor agonist 10 mg

50 mg

180

720

4366 SaG Potent Smoothened receptor agonist; activates the hedgehog signaling pathway

1 mg 155

Antagonists 1623 Cyclopamine Inhibitor of hedgehog (hh) signaling; antagonizes smoothened activity

1 mg 180

5554 IhR 1 Potent Smo antagonist 10 mg

50 mg

125

470

1974 SaNT-1 Inhibitor of hedgehog (hh) signaling; antagonizes smoothened activity

10 mg

50 mg

175

665


GPCR ReSeaRCh

tocris.com | 29

GPCR SignalingGPCRs mediate signal transduction from the cytosol to the cell interior. Agonist binding to GPCRs results in the coupling of heterotrimeric G proteins, which are subsequently released by GDP/GTP exchange. The G protein subunits activate effector proteins, such as cyclases and phospholipases to induce intracellular signaling cascades.

Adenylyl Cyclase

Activators 1099 Forskolin adenylyl cyclase activator 10 mg

50 mg

145

560

1603 NKh 477 Water-soluble adenylyl cyclase activator 10 mg

50 mg

210

820

Inhibitors 1435 SQ 22536 adenylyl cyclase inhibitor 10 mg

50 mg

145

545

cAMP

Other 5255 6-Bnz-caMP sodium salt Cell permeable caMP analog 1 mg 140

1140 8-Bromo-caMP, sodium salt Cell-permeable caMP analog 10 mg

50 mg

80

240

1337 caMPS-Rp caMP antagonist 1 mg 145

1333 caMPS-Sp Cell-permeable caMP analog 1 mg 145

1141 Dibutyryl-caMP, sodium salt Cell-permeable caMP analog 10 mg

50 mg

100

325

G Protein (Heterotrimeric)

Inhibitors 4567 CCG 50014 Potent and selective inhibitor of regulator of G-protein signaling 4 (RGS4) protein

10 mg

50 mg

175

665

4773 eSI 09 ePaC inhibitor 10 mg

50 mg

165

635

3090 Gallein Inhibitor of βγ signaling 50 mg 85

Other 3097 Pertussis Toxin Catalyzes aDP-ribosylation of Gi, Go and Gt 50 µg 335

GRK

Inhibitors 5642 CMPD101 Potent and selective GRK2/3 inhibitor 10 mg 140

3594 GRK2i GRK2 inhibitory polypeptide; Gβγ antagonist 1 mg 215

IP3 Receptor

Antagonists 1224 2-aPB IP3 receptor antagonist; also TRP channel modulator 10 mg

50 mg

80

240

Other 1280 (-)-Xestospongin C Reported inhibitor of IP3-dependent Ca2+ release 10 µg 195

Phospholipases

Inhibitors 1437 D609 Selective PC-PLC inhibitor 10 mg

50 mg

140

450

3022 edelfosine Selective PI-PLC inhibitor; also PaF receptor agonist 10 mg 125

3600 FIPI Phospholipase D inhibitor 10 mg

50 mg

215

865

1268 U 73122 Phospholipase C inhibitor 10 mg

50 mg

145

530

4133 U 73343 analog of U 73122 (Cat. No. 1268) 10 mg

50 mg

140

520

3575 VU 0155069 Potent and selective PLD1 inhibitor 10 mg

50 mg

195

775

4171 VU 0364739 Potent and selective PLD2 inhibitor 10 mg

50 mg

225

900

2522 YM 26734 Secretory phospholipase a2 (sPLa2) inhibitor 10 mg 180



30 |

Activation

Inhibition

Movement

Blocked effect

Gαs

GαiGαq Gα

AC PLC Raf ASK1

MEK1 MEK4 PI 3-K RhoA c-Src

ERK JNK Akt ROCK

cAMP ATP

PKA EPAC

IP3 DAG

Ca2+ PKC

β-arrestin

GRK5/6

GRK5/6

G Protein-dependent Signaling β-Arrestin-dependent Signaling

β-arrestin PP

Bias SignalingBiased agonism or functional selectivity is the phenomenon whereby ligands can selectively activate certain signaling pathways, while others remain inactive. Biased ligands can stabilize their GPCR in different active conformations, resulting in bias towards certain pathways such as G protein- or β-arrestin-dependent signaling.

Allosteric Modulation and Bias Signaling:as well as many orthosteric ligands being identified as bias agonists, allosteric ligands have also been shown to exhibit signal bias (for an overview of allosteric modulation see pg 27). Certain allosteric modulators have the ability to direct orthosteric agonist signaling towards specific signaling pathways. For example ORG 27569 (Cat. No. 2957) acts as a negative allosteric modulator (NaM) of orthosteric agonist-mediated CB1 Gαs signaling and a positive allosteric modulator (PaM) on β-arrestin signaling, while Gadolinium (Cat. No. 4741) is a PaM of agonist-mediated mGlu1α Gαq signaling and a NaM on Gαs signaling. The discovery of allosteric ligands that can direct orthosteric ligand signal bias offers the potential for the augmentation of desirable physiological signaling pathways to produce more effective therapeutic drugs.

Biased Signaling Schematic

Schematic representing biased signaling towards G protein- and β-arrestin signaling. GPCR signaling classically results in the downstream activation of G proteins, which stimulate intracellular effectors such as aC and PLC. activated GPCRs are phosphorylated by GRKs, recruiting β-arrestin to the receptor and stimulating further signaling pathways such as MaPK, PI 3-K, Rhoa and c-Src signaling. Ligands have recently been developed that can selectively activate G protein- or β-arrestin-dependent signaling, while having no significant effect on the other pathway. Certain ligands can also stimulate specific Gα proteins over others. This phenomenon was termed biased agonism. These biased ligands can induce GPCRs to adopt certain active conformations that preferentially activate different intracellular signaling pathways.abbreviations: aC, adenylyl cyclase; akt, protein kinase B; caMP, cyclic adenosine monophosphate; aSK1, apoptosis signal-regulating kinase 1; aTP, adenosine triphosphate; DaG, diacylglycerol; ePaC, exchange factor directly activated by caMP 1; eRK, extracellular signal–regulated kinase; GRK, G protein-coupled receptor kinase; IP3, inositol trisphosphate; JNK, c-Jun N-terminal kinase; MeK, mitogen-activated protein kinase kinase; PI 3-K, phosphatidylinositol-4,5-bisphosphate 3-kinase; PKa, protein kinase a; PKC, protein kinase C; PLC, phospholipase C; Rhoa, Ras homolog gene family, member a; ROCK, Rho-associated protein kinase.

GPCR ReSeaRCh

tocris.com | 31

GPCRCrystalStructures:

Bortolato et al (2014) Structure of Class B GPCRs: new horizons for drug discovery. Br.J.Pharmacol. 171 3132Granier and Kobilka (2012) A new era of GPCR structural and chemical biology. Nat.Chem.Biol. 8 670Stevens et al (2013) The GPCR Network: a large-scale collaboration to determine human GPCR structure and function. Nat.Rev.Drug Discov. 12 25Tautermann (2014) GPCR structures in drug design, emerging opportunities with new structures. Bioorg.Med.Chem.Lett. 24 4073

GPCRAllostery:

Christopoulos (2014) Advances in G protein-coupled receptor allostery: from function to structure. Mol.Pharmacol. 86 463Christopoulos et al (2014) International Union of Basic and Clinical Pharmacology. XC. multisite pharmacology: recommendations for the nomenclature of receptor allosterism and allosteric ligands. Pharmacol.Rev. 66 918Kollias-Baker et al (1994) Allosteric enhancer PD 81,723 acts by novel mechanism to potentiate cardiac actions of adenosine. Circ.Res. 75 961Müller et al (2012) Allosteric modulators of rhodopsin-like G protein-coupled receptors: opportunities in drug development. Pharmacol.Ther. 135 292Wooten et al (2013) Emerging paradigms in GPCR allostery: implications for drug discovery. Nat.Rev.Drug Discov. 12 630

BiasSignaling:

Kenakin and Christopoulos (2013) Signalling bias in new drug discovery: detection, quantification and therapeutic impact. Nat.Rev.Drug Discov. 12 205Khoury et al (2014) Allosteric and biased G protein-coupled receptor signaling regulation: potentials for new therapeutics. Front.Endocrinol. 5 1Rankovic et al (2014) Biased agonism: An emerging paradigm in GPCR drug discovery. Bioorg.Med.Chem.Lett. 26 241Sonoda et al (2014) β-Arrestin-1 mediates glucagon-like peptide-1 signaling to insulin secretion in cultured pancreatic beta cells. Proc.Natl.Acad.Sci.U.S.A. 105 6614

References and Further Reading

Analgesia:

• Morphine (Cat. No. 5158), an opioid receptor agonist, is commonly used clinically to relieve pain

• β-arrestin knock-out mice administered morphine experience enhanced analgesia and fewer side effects, such as respiratory and gastrointestinal dysfunction

• The development of opioid receptor bias agonists that selectively activate G protein signaling may result in improved analgesic drugs without the adverse side effects

Antipsychotics:

• Dopamine D2 receptor antagonists are clinically used as antipsychotics, but are associated with motor side effects such as catalepsy and dyskinesias

BiasSignaling(cont.):

Therapeutic Applications:Biased agonism is of great interest therapeutically as it offers the potential to preferentially activate signaling pathways that induce the desired physiological effect, while having no effect on those that cause adverse side effects. Biased agonists have the potential to revolutionize the drug discovery process, through the generation of safer and more effective drugs.

• β-arrestin biased D2 agonists have been recently developed that exhibit antipsychotic activity in mice without the motor side effects

Cardiovascular Disease:

• angiotensin II receptor type 1 (aT1) antagonists have long been used in the treatment of hypertension, however reduced cardiac output is a side effect

• The β-arrestin biased aT1 antagonist TRV027 has been shown to reduce blood pressure and enhance cardiac performance in rats

• Furthermore β-arrestin biased aT1 agonists have been found to protect against cell death during cardiac injury, which could be applied to the treatment of cardiac ischemia

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