advanced receptor psychopharmacology...advanced receptor psychopharmacology. 1. otsuka...
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© 2017 Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD
Advanced Receptor Psychopharmacology
1
Otsuka Pharmaceutical Development & Commercialization, Inc. Lundbeck, LLC.
February 2017 MRC2.CORP.D.00208
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This program was developed with the support of Otsuka Pharmaceutical Development &
Commercialization, Inc. and Lundbeck, LLC. The speakers are either employees or
paid contractors of Otsuka Pharmaceutical Development & Commercialization, Inc.
2
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• Receptor Types and Subtypes– Ionotropic vs Metabotropic
– Autoreceptor vs Heteroreceptor
• Intrinsic Activity and Functional Selectivity
• Neurotrophic Factors
• Synaptic Plasticity
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Table of Contents
The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
© PsychU. All rights reserved.
The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
• Ionotropic receptor– Fast and direct action1,2
– Examples include some glutamate receptors (AMPA, NMDA, Kainate) and nicotinic acetylcholine receptors3,4
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1. Purves D, Augustine GJ, Fitzpatrick D, et al (eds). Neuroscience. 3rd edition. Sinauer Associates; 2004.
2. Turk E, et al. Hum Brain Mapp. 2016;37(5):1856-65.3. Vignes M, et al. Nature. 1997;388(6638):179-82.4. Sargent PB. Annu Rev Neurosci. 1993;16:403-43. Image from: Purves D, et al; 20041
Receptor Types: Ionotropic vs Metabotropic
AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA, N-methyl-D-aspartate.
The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
© PsychU. All rights reserved.
The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
• Metabotropic receptor– Comparatively slow and
indirect action1
– Examples include some Glutamate receptors (mGluR) and muscarinic acetylcholine receptors2
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1. Purves D, Augustine GJ, Fitzpatrick D, et al (eds). Neuroscience. 3rd edition. Sinauer Associates; 2004.2. Sherman SM. Trends Neurosci. 2001;24(2):122-6.
Image from: Purves D, et al. 20041
Receptor Types: Ionotropic vs Metabotropic (continued)
mGluRs, metabotropic glutamate receptors.
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Autoreceptor
• Receptor is only sensitive to the neurotransmitter of the cell type it’s located on1
• Example:– A serotonin (5-HT) receptor can be
located on a presynaptic 5-HT neuron2
• Result:– 5-HT binding to an autoreceptor on
its own neuron can influence the activity or concentration of 5-HT release3
Heteroreceptor
• Receptor is only sensitive to neurotransmitters of cell types other than the type it’s located on4
• Example:– A 5-HT receptor can be located on
a dopamine (DA) neuron5,6
• Result:– 5-HT binding to a heteroreceptor
on a DA neuron can influence the activity or concentration of DA release6
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1. Starke K, et al. Physiol Rev. 1989;69(3):864-989.2. Barnes NM, et al. Neuropharmacology. 1999;38(8):1083-152.3. Sharp T, et al. Trends Pharmacol Sci. 2007;28(12):629-36.
Receptor Types: Auto vs Hetero
4. Gilsbach R, et al. Br J Pharmacol. 2012;165(1):90-102.5. Esposito E, et al. Prog Brain Res. 2008;172:3-6.6. Bostwick JM, et al. J Clin Psychiatry. 1999;60(12):857-60.
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1. Brunton LL, Lazo, JS, Parker KL (eds). Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 11th edition. McGraw-Hill; 2005.2. Jackson CM, et al. Accred Qual Assur. 2007; 2:283–294.3. Kore PP, et al. Open Journal of Medicinal Chemistry. 2012;2:139-148.4. Lieberman JA. CNS Drugs. 2004;18(4):251-67.
• Intrinsic activity of drug at a receptor– The physiologic effect a ligand elicits once bound to its receptor1,2
– Ligand can partially or fully stimulate (agonism) or inhibit (antagonism, inverse agonism) receptor activity1,3,4
Intrinsic Activity
Partial activationFull activation No activation
AntagonistPartial agonistAgonist
Reduced likelihood of activation
Inverse agonist
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Spectrum of Intrinsic Activity
Szkudlinski MW. Front Endocrinol (Lausanne). 2015;6:155.
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Image from: Szkudlinski MW; 2015
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Neurotrophic Factors
• Greek “trophé,” meaning “nourishment”• Regulate neuronal differentiation and growth• Signaling via neurotrophic factors can activate:
– cell survival/death– synapse stabilization/elimination– process growth/retraction
• Types:– Nerve growth factor (NGF)– Brain-derived neurotrophic factor (BDNF)– Neurotrophin 3 (NT-3)– Neurotrophin 4/5 (NT-4/5)
Purves D, Augustine GJ, Fitzpatrick D, et al (eds). Neuroscience. 3rd edition. Sinauer Associates; 2004.
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Neurotrophin Signaling Pathway
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(B)
Outside
Inside
TrkB receptor
PI 3 kinase ras PLC
PKBAkt kinase
Kinases
MAP Kinase
IP3 DAG
Ca2+
release PKC
Cellsurvival
Neuriteoutgrowth
and neuronaldifferentiation
Activity–dependentplasticity
TrkC receptorTrkA receptor
(A) NGF BDNF NT-4/5 NT-3
Neuritegrowth
Cell cycle arrest
Celldeath
RhoASC1 NADE
p75 receptor
BDNF
NGF NT-4/5NT-3
NGF, nerve growth factor; BDNF, brain-derivedneurotrophic factor; NT, neurotrophin; Trk, tyrosine receptor kinase; PI 3, phosphoinositide 3; ras, rat sarcoma; PLC, phospholipase C; PKB, protein kinase B; Akt, AKT serine/threonine kinase 1; MAP, mitogen-activated protein; IP3, inositol trisphosphate; DAG, diacylglycerol, Ca2+, calcium; PKC, protein kinase C; SC1, Schwann cell 1; NADE, neurotrophin-associated cell death executor; RhoA, Ras homolog gene family member A.
Purves D, Augustine GJ, Fitzpatrick D, et al (eds). Neuroscience. 3rd edition. Sinauer Associates; 2004.
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The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; PSD, postsynaptic density
1. Collingridge GL, et al. Nat Rev Neurosci. 2004;5(12):952-62.2. Sweatt JD. J Neurochem. 2001;76(1):1-10.3. Vitureira N, et al. J Cell Biol. 2013;203(2):175-86.
Synaptic plasticity: complex, ongoing, structural/functional alterations in the nervous system1,2
• Long-term potentiation (LTP): robust and long-lasting form of synaptic plasticity2
– Leading candidate for a cellular mechanism contributing to learning and memory2
– Glutamate receptors are required for the induction and expression of this form of plasticity, and GABA receptors are involved in their modulation3
Synaptic Plasticity and Long-term Potentiation
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Image from: Vitureira N, et al; 20133
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• Specific subtypes of neurotransmitters can have different signaling pathways (eg, ionotropic vs. metabotropic) or functions (eg, autoreceptor vs heteroreceptor), depending on their neuroanatomical location1,2,3
• Receptor activation via ligand binding can variably influence a receptor’s intrinsic activity and functional selectivity2–5
• Neurotrophic factor signaling can regulate activities such as neuronal differentiation, growth, survival, and plasticity2,6
Summary
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1. Starke K, et al. Physiol Rev. 1989;69(3):864-989.2. Purves D, Augustine GJ, Fitzpatrick D, et al (eds). Neuroscience. 3rd edition. Sinauer Associates; 2004.3. Gilsbach R, et al. Br J Pharmacol. 2012;165(1):90-102.4. Jackson CM, et al. Accred Qual Assur. 2007; 2:283–294.5. Gilchrist A. Trends Pharmacol Sci 2007;28(8):431-437.6. Lo DC. Neuron. 1995;15(5):979-81.
The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
© 2017 Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD
Advanced Receptor Psychopharmacology
14
Otsuka Pharmaceutical Development & Commercialization, Inc. Lundbeck, LLC.
February 2017 MRC2.CORP.D.00208