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The Organic Chemistry of Drug Design and Drug Action
Chapter 3
Receptors
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Receptors1878 Langley
Study of antagonistic action of alkaloids on cat salivary flow suggests the compounds interacted with some substance in the nerve endings
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Receptors
1897 Ehrlich
Side chain theory - Cells have side chains that contain groups that bind to toxins - termed receptors
1906 Langley
Studying antagonistic effects of curare on nicotine stimulation of skeletal muscle
Concluded receptive substance that received stimulus, and by transmitting it, caused muscle contraction
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Two fundamental characteristics of a receptor:
Recognition capacity - binding Amplification - initiation of response
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Integral proteins embedded in phospholipid bilayer of membranes
Figure 2.26
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Drug-Receptor InteractionsPharmacodynamics
Kd =[drug][receptor]
[drug-receptor complex] (3.1)
Driving force for drug-receptor interaction - low energy state of drug-receptor complex (binding energy)Kd - measure of affinity to receptor (a dissociation constant)
SCHEME 3.1 Equilibrium between a drug, a receptor, and a drug–receptor complex
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Forces Involved in Drug-Receptor Complex
Molecular surfaces must be close and complementary
G° = -RTlnKeq (3.2)
Decrease in G° of ~ 5.5 kcal/mol changes binding equilibrium from 1% in drug-receptor complex to 99% in drug-receptor complex
Forces in drug-receptor complex generally weak and noncovalent (reversible)
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Ionic Interaction
Basic groups, e.g., His, Lys, Arg (cationic)
Acidic groups, e.g., Asp, Glu (anionic)
Figure 3.1 G° ≈ -5 kcal/mol
FIGURE 3.1 Example of an electrostatic (ionic) interaction. Wavy line represents the receptor cavity.
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Ion-Dipole and Dipole-Dipole Interactions
Figure 3.2 G° ≈ -1 to -7 kcal/mol
FIGURE 3.2 Examples of ion–dipole and dipole–dipole interactions. Wavy line represents the receptor cavity.
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Hydrogen BondingType of dipole-dipole interaction between H on X-H (X is an
electronegative atom) and N, O, or F
Figure 3.3 G° ≈ -3 to -5 kcal/mol
FIGURE 3.3 Examples of hydrogen bonds. Wavy line represents the receptor cavity.
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Intramolecular hydrogen bonding
FIGURE 3.4 Two examples (A and B) of how intramolecular hydrogen bonding can mimic a bioisosteric heterocycle.
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a-helix
3.5 is an example of an α-helix in a protein—Copyright 2007 from Molecular Biology of the Cell, Fifth Edition by Alberts, et al. Reproduced by permission of Garland Science/Taylor & Francis LLC.
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-sheet
3.6 is an example of a β-sheet in a protein—Copyright 2007 from Molecular Biology of the Cell, Fifth Edition by Alberts, et al. Reproduced by permission of Garland Science/Taylor & Francis LLC.
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DNA
3.7 is an example of a double helix in DNA—Copyright 2007 from Molecular Biology of the Cell, Fifth Edition by Alberts, et al. Reproduced by permission of Garland Science/Taylor & Francis LLC.
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Charge-Transfer Complexes(molecular dipole-dipole interaction)
chlorothalonil-fungicide
acceptor donor
Figure 3.6G° ≈ -1 to -7 kcal/mol
FIGURE 3.6 Example of a charge-transfer interaction. Wavy line represents the receptor cavity.
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Hydrophobic “Interactions”Increase in entropy of H2O molecules decreases free energy. Therefore the complex is stabilized.
FIGURE 3.7 Formation of hydrophobic interactions. From Korolkovas, A. (1970). Essentials of Molecular Pharmacology, p. 172. Wiley, New York. This material is reproduced with permission of John Wiley & Sons, Inc. and by permission of Kopple, K. D. 1966. Peptides and Amino Acids. Addison-Wesley, Reading, MA.
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Hydrophobic Interaction
butamben - topical anesthetic G° ≈ -0.7 kcal/mol per CH2/CH2 interaction
FIGURE 3.8 Example of hydrophobic interactions. The wavy line represents the receptor cavity.
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π-π-Interactions
FIGURE 3.9 Example of π–π stacking. The wavy line represents the receptor cavity.
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Cation-π-interactions
FIGURE 3.10 Example of a cation–π interaction. The wavy line represents the receptor cavity.
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Halogen bonding
FIGURE 3.11 Example of halogen bonding. A compound bound into phosphodiesterase 5. The wavy line represents the enzyme cavity.
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Van der Waals (London Dispersion) Forces
G° ≈ -0.5 kcal/mol per CH2/CH2 interaction
As molecules approach, temporary dipoles in one molecule induce opposite dipoles in another; therefore, producing an intermolecular attraction
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Dibucaine - local anestheticFIGURE 3.12 Example of potential multiple drug–receptor interactions. The van der Waals interactions are excluded.
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Dose-Response Curve
Use any measure of response(LD50, ED50, etc.)
Means of measuring drug-receptor interactions
FIGURE 3.13 Effect of increasing the concentration of a neurotransmitter (ACh) on muscle contraction. The Kd is measured as the concentration of neurotransmitter that gives 50% of the maximal activity.
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Full Agonist
FIGURE 3.14 Dose–response curve for a full agonist (W).
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Competitive Antagonist
Noncompetitive Antagonist
Different binding sites
Antagonists
X
NT + R NT R
X R
FIGURE 3.15 (A) Dose-response curve for an antagonist (X); (B) effect of a competitive antagonist (X) on the response of a neurotransmitter (acetylcholine; ACh); (C) effect of varying concentration of a competitive antagonist X in the presence of a fixed, maximally effective concentration of agonist (ACh); and (D) effect of various concentrations of a noncompetitive antagonist (X’) on the response of the neurotransmitter (ACh).
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Partial Agonistlow [neurotransmitter]added
agonist effect
antagonist effect
high [neurotransmitter]added
FIGURE 3.16 (A) Dose–response curve for a partial agonist (Y); (B) effect of a low concentration of neurotransmitter on the response of a partial agonist (Y); and (C) effect of a high concentration of neurotransmitter on the response of a partial agonist (Y). In (C), the concentration of the neurotransmitter (a,b,c) is c > b > a.
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Inverse Agonistsfull inverse agonist
partial inverse agonist
Addition of an agonist or antagonist to an inverse agonist (a, b, c are increasing concentrations of agonist added)
FIGURE 3.17 (A) Dose–response curve for a full inverse agonist (Z); (B) effect of a competitive antagonist on the response of a full inverse agonist (a, b, and c represent increasing concentrations of the added antagonist or natural ligand to Z); and (C) dose–response curve for a partial inverse agonist (Z′).
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To effect a certain response of a receptor, design an agonist
To block a particular response of a natural ligand of a receptor, design an antagonist
To produce the opposite effect of the natural ligand, design an inverse agonist
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Agonists - often structural similarity
Antagonists - littlestructural similarity
Table 3.1
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How can agonists and antagonists bind to same site and one show response, other not?
agonist antagonist enantiomer
• All naturally-occurring chemicals in the body are agonists• Most xenobiotics are antagonists• Drugs that bind to multiple receptors side effects
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Two stages of drug-receptor interactions:
1) complexation with receptor 2) initiation of response
affinity efficacyintrinsic activity
(Stephenson)(Ariëns)
All are full agonists
5 different drugs = 1 full agonist < 1 partial agonists
FIGURE 3.19 Theoretical dose–response curves illustrate (A) drugs with equal affinities and different efficacies (the top compound is a full agonist, and the others are partial agonists) and (B) drugs with equal efficacies (all full agonists) but different affinities.
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Affinity and efficacy are uncoupled: a compound can have great affinity but poor efficacy (and vice versa).
A compound can be an agonist for one receptor and an antagonist or inverse agonist for another receptor.
A full or partial agonist displays positive efficacy.
An antagonist displays zero efficacy.
A full or partial inverse agonist displays negative efficacy.
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Drug-Receptor Theories
Occupancy Theory (1926)Intensity of pharmacological effect is directly proportional to number of receptors occupied
Does not rationalize how two drugs can occupy the same receptor and act differently
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Rate Theory (1961)
Activation of receptors is proportional to the total number of encounters of a drug with its receptor per unit time.
Does not rationalize why different types of compounds exhibit the characteristics they do.
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Induced Fit Theory (1958)
• Agonist induces conformational change - response
• Antagonist does not induce conformational change - no response
• Partial agonist induces partial conformational change - partial response
FIGURE 3.20 Schematic of the induced-fit theory. Koshland, Jr., D. E., and Neet, K. E., Annu. Rev. Biochem., Vol. 37, 1968. Annual Review of Biochemistry by Annual Reviews. Reproduced with permission of Annual Reviews via Copyright Clearance Center, 2013.
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Macromolecular Perturbation Theory Two types of conformational perturbation (Belleau) Specific conformational perturbation allows molecule
to induce a response Nonspecific conformational perturbation does not
result in a response How to explain an inverse agonist?
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Activation-Aggregation TheoryMonad, Wyman, Changeux (1965) Karlin (1967)
Receptor is always in a state of dynamic equilibrium between activated form (Ro) and inactive form (To).
Ro Tobiologicalresponse
no biologicalresponse
Agonists shift equilibrium to Ro
Antagonists shift equilibrium to To
Partial agonists bind to both Ro and To
Binding sites in Ro and To may be different, accounting for structural differences in agonists vs. antagonists
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Two-state (Multi-state) Receptor ModelR and R* are in equilibrium (equilibrium constant L), which defines the basal activity of the receptor.
Full agonists bind only to R*
Partial agonists bind preferentially to R*
Full inverse agonists bind only to R
Partial inverse agonists bind preferentially to R
Antagonists have equal affinities for both R and R* (no effect on basal activity)
In the multi-state model there is more than one R state to account for variable agonist and inverse agonist behavior for the same receptor type.
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Drug and Receptor ChiralityDrug-Receptor Complexes
Receptors are chiral (all L-amino acids)
Racemic mixture forms two diastereomeric complexes
[Drug]R + [Drug]S + [Receptor]S
[Drug]R [Receptor]S + [Drug]S [Receptor]S
Have different energies and stabilities
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Topographical and Stereochemical ConsiderationsSpatial arrangement of atoms
Common structural feature of antihistamines (antagonists of H1 receptor)
Pharmacophore - parts of the drug that interact with the receptor and cause a response
Figure 3.22
CH-O, N-, CH- 2 or 3 carbons
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Chiral antihistamineKd for enantiomers are different - two diastereomers are formed
(S)-(+)-isomer 200x more potent than (R)-(-)-
More potent isomer -
Less potent isomer -
eutomer
distomer
Ratio of potencies of enantiomers -
High eudismic ratio when antagonist has stereogenic center in pharmacophore
eudismic ratio
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Distomer is really an impurity (“isomeric ballast”)
May contribute to side effects and/or toxicity
N
O
O
HNO O
H
N
O
O
HN OO
H
3.13
(R)-(+)-thalidomidesedative/hypnotic
(S)-(-)-thalidomideteratogen
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Enantiomers of ketamine
S-ketamine is several fold more potent than R-ketamine
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Prilocaine, a local anesthetic
Both enantiomers are active, but only one is toxic
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Drugs useful as mixtures of enantiomers
Both are local anesthetics,But l-form is vasoconstrictor
Diuretic, but one enantiomer causes uric acidretention, the other inhibits it
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Enantiomers can have different activities
S-enantiomer: NSAIDR-enantiomer: Reduces bone loss in periodontal disease
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Enantiomers can have different activities
dextropropoxyphene (Darvon®)analgesic
levopropoxyphene (Novrad®)antitussive (anticough)
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Enantiomers can have opposite activities
barbiturate
S-(+)-convulsive
R-(-)-narcotic
(actually inverse agonist)
One enantiomer may antagonize the other with no overall effect observed.
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Enantiomers can have opposite activities
(+)-isomer: Narcotic agonist analgesic(-)-isomer: Narcotic antagonist
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Enantiomers can have opposite activities
R-enantiomer: Serotonin agonist at 5HT-1aS-enantiomer: Serotonin antagonist at 5HT-1a
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Stereospecificity of one compound can vary for different receptors
(+) - 3.24 butaclamol - antipsychotic(-) is almost inactive
Eudismic ratio (+/-) is 1250 for D2-dopaminergic, 160 for D1-dopaminergic, and 73 for -adrenergic receptors
Eudismic ratio (-/+) is 800
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Hybrid drugs - different therapeutic activities
propranolol (X = NH )antihypertensive
Antagonist of -adrenergic receptor (-blocker) - triggers vasodilation
Eudismic ratio (-/+) is 100
But propanolol also is a local anesthetic for which eudismic ratio is 1
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Pseudo-hybrid drug - multiple isomeric forms involved in biological activity
labetalol - antihypertensive
R,R- mostly -blocker (eutomer for -adrenergic block)
S,R- mostly -blocker (eutomer for -adrenergic block)
S,S- and R,S- almost inactive (isomeric ballast)
FIGURE 3.23 Four stereoisomers of labetalol
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Epinephrine, a natural hybrid drug
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Racemates as Drugs 90% of -blockers, antiepileptics, and oral
anticoagulants on drug market are racemates 50% of antihistamines, anticholinergics, and local
anesthetics on drug market are racemates In general, 30% of drugs are sold as racemates
Racemic switch - a drug that is already sold as a racemate is patented and sold as a single enantiomer (the eutomer)
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Omeprazole, a chiral switch
RS, Prilosec, now genericS-enantiomer, Nexium
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Single enantiomer drugs are expected to have lower side effects
Antiasthma drug albuterol binds to 2-adrenergic receptors, leading to bronchodilation
The (R)-(-)-isomer is solely responsible for effects; the (S)-(+)-isomer causes pulse rate increases, tremors, and decreased blood glucose and potassium levels
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Sometimes, it is better to use the racemate than one isomer. In the case of the antihypertensive drug nebivolol, the (+)-isomer is a -blocker; the (-)-isomer causes vasodilation by a different mechanism. Therefore, it is sold as a racemate to take advantage of both vasodilating pathways.
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Prozac is the racemic drug. The R-enantiomer showed cardiotoxicity so the chiral switch failed
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Verapamil is used as a racemate
S-enantiomer is an antihypertensiveR-enantiomer inhibits resistance of cancer cells
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Receptor Interaction
Enantiomers cannot be distinguished with only two binding sites.
Figure 3.24
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Three-point attachment concept
Figure 3.25
Receptor needs at least three points of interaction to distinguish enantiomers.
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Unnatural enantiomers of natural products may have useful activities
Both of these are more active than the natural enantiomers!
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Diastereomers
The antihistamine activity of (E)-triprolidine (3.36a) is 1000-fold greater than the (Z)-isomer (3.36b).
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Diastereomers
The antipsychotic activity of 3.37a is 12 times more than 3.37b
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Diastereomers
Diethylstilbestrol (3.38a) is a much more potent estrogen than the Z-isomer (3.38b)
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Conformational Isomers Pharmacophore is defined by a particular conformation
of a molecule (the bioactive conformation) The conformer that binds need not be the lowest energy
conformer Binding energy can overcome the barrier to formation of
a higher energy conformer
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Figure 3.26
Note that the bioactive conformation bound to the peroxisome proliferator activated receptor gamma (PPAR) is not the lower energy extended conformation.
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If the lead has low potency, it may be because of the low population of the active conformer. If the bioactive conformer is high in energy, the Kd will appear high (poor affinity) because the population of the ideal conformer is low.
SCHEME 3.2 Cyclohexane conformations. a, chair (substituent equatorial); b, half-chair; c, boat; d, half-chair; e, chair (substituent axial).
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To determine the active conformation, make conformationally rigid analogs. The flexible lead molecule is locked into various conformations by adding bonds to rigidify it.
First we will use this approach to identify the bioactive conformation of a neurotransmitter, then a lead molecule.
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Consider acetylcholine binding to muscarinic and nicotine receptors
Me3NCH2CH2OCCH3
O
Me3NOAc
acetylcholine
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Four conformers of acetylcholine (just staggered conformers)
Lowest energy conformer
Newman projections
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Conformationally rigid analogs
All exhibited low muscarinic receptor activity, but 3.43a was most potent (0.06 times potency of ACh).
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Analogues of acetylcholine
The threo isomer (3.44) is 14 time more potent than acetylcholine.
The erythro isomer (3.45) is 0.036 times as potent as acetylcholine.
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To minimize the number of extra atoms, the cyclopropane analog was made.
The (+)-trans isomer (3.46) has about the same muscarinic activity as acetylcholine; (-)-trans isomer 1/500th potency.
Excellent support for the anti-conformer as the bioactive conformer.
()-cis isomer (3.47) has negligible activity. Therefore, acetylcholine binds to the muscarinic receptor in an extended form (3.42a)
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However, both the trans and cis cyclopropane analogs are weakly active with the nicotinic receptor for acetylcholine.
Therefore, a conformation other than the anti-conformation must bind to that receptor (i.e., a higher energy conformer).
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Conformationally Rigid Analogs in Drug Design
moderate tranquilizing activity
Maybe it is because the piperidino ring needs to be in a higher energy conformation for good binding.
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Possible conformers of piperidino ring
F C
O
(CH2)3R =
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Conformationally Rigid Analogs
order of potency3.51 > 3.52 > 3.50
Therefore, the less stable axial conformer binds better than the equatorial conformer.
Lead modification should involve making analogs in which the hydroxyl group is preferred in an axial orientation.
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Conformations of PCP
FIGURE 3.27 PCP, 3.53 and three conformationally rigid analogs of PCP
All these analogs bind poorly to the NMDA receptor, but bind well to the σ-receptor.
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Conformations of peptides
FIGURE 3.28 Use of a triazole as a conformationally rigid bioisostere to lock in an amide bond conformation
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Atropisomers
FIGURE 3.29 General example of atropisomerization
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What makes atropisomers stable?
FIGURE 3.30 Example of a nonatropisomer, an unstable atropisomer, and a stable atropisomer
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Telenzepine racemizes very slowly
FIGURE 3.31 Exceedingly slow isomerization of atropisomers of telenzepine (3.57)
(+) isomer is 500 times more active at muscarinic acetylcholine receptors
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Atropisomers in drug optimization
The active atropisomer of 3.58 is 3.59. 3.60 has two atropisomers3.61 has only a single isomer
A neurokinin 1antagonist is alead for an antidepressant
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Avoiding atropisomers—make rotations fast
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Symmetrization to avoid atropisomers
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Ring Topology
chlorpromazine - tranquilizeramitriptyline - antidepressant with a tranquilizing side effect
imipramine - pure antidepressant
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bending of ring planes torsional angleannellationangle of ring axes
tranquilizers - only mixed - and antidepressants - , ,
Figure 3.32
You must consider the 3-dimensional structures of rings.
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Case History of Rational Drug Design - Cimetidine
(no QSAR, computer graphics, or X-ray crystallography)
Another action of histamine - stimulation of gastric acid secretion
Antihistamines have no effect on H2 receptor
Nobel Prize (1988) to James Black for antagonist discovery
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H1 and H2 receptors differentiated by agonist and antagonists
H1 receptor agonist (no effect on H2
receptor)
H2 - receptor agonist (no effect on H1 receptor)
H2 - receptor antagonists would be antiulcer drugs
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Bioassay used to screen compounds
Histamine was infused into anesthetized rats to stimulate gastric acid secretion, then the pH of the perfusate from the stomach was measured before and after administration of the test compound.
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Lead Discovery
Histamine analogs synthesized at Smith, Kline, and French (now GlaxoSmithKline)
Took four years and 200 compounds
3.75 was very weakly active (actually, partial agonist)
N-guanylhistamine
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Isosteric replacement
Isothiourea 3.76 is more potent than the cyclic analogue 3.77
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imidazole retained for recognition
not + charged
homolog
Had weak antagonistic activity without stimulatory activity.
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Homologation
further homologation
R = CH3 burimamide
purely competitive antagonist for H2 receptor
Tested in humans - poor oral activity
Could be pharmacokinetics or pharmacodynamics
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Consider pharmacodynamics
Imidazole ring can exist in 3 forms
FIGURE 3.33 Three principal forms of 5-substituted imidazoles at physiological pH
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Thioureido group can exist as 4 conformers
Side chain can be in many conformations
Maybe only a small fraction in the bioactive form
FIGURE 3.34 Four conformers of the thioureido group
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To increase potency of burimamide
Compare population of the imidazole form in burimamide at physiological pH to that in histamine.
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Hammett Study of Electronic Effect of Side Chainfavored forR = e- -withdrawing
favored forR = e- -donating
pKa of imidazole = 6.80
pKa of imidazole in histamine = 5.90
Therefore, side chain is e- -withdrawing, favoring 3.80a.
pKa of imidazole in burimamide = 7.25
Therefore, side chain is e- -donating, favoring 3.80c.
Need to make side chain e- -withdrawing.
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Isosteric replacement to lower the pKa of the imidazole
A second way to increase population of 3.80a is to put an e- -donating group at 4-position.
metiamide (3.82, R = CH3)
pKa of imidazole in metiamide = 6.80
8-9 times more potent than burimamide
thiaburimamide (R = H)
pKa of imidazole in thiaburimamide = 6.25
thiaburimamide is 3 times more potent than burimamide
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Oxaburimamide is less potent than burimamide, even though O is more electronegative than S
Conformationally-restricted analog forms by intramolecular H-bonding.
Does not occur with thiaburimamide.
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Metiamide (3.82)tested in 700 patients with duodenal ulcers - very effective.
However, side effect in a few cases (granulocytopenia).
Thought the side effect was caused by the thiourea group.
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Isosteric replacement (X = O, X = NH) is 20 times less potent.
When X = NH, basic
To lower basicity, add e- -withdrawing group
X = N-CN (cimetidine) (pKa -0.4)
X = N-NO2 (pKa -0.9)
Both are comparable to metiamide in potency but without the side effect.
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FIGURE 3.35 Linear free energy relationship between H2 receptor antagonist activity (pA2) and the partition coefficient. Reprinted with Permission of Elsevier. This article was published in Pharmacology of Histamine Receptors, Ganellin, C. R., and Parsons, M. E. (1982), p. 83, Wright-PSG, Bristol.
Linear free energy relationship between potency and lipophilicity
cimetidine
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A cyclic analogue is less active
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Other H2 receptor antagonists made using cimetidine as the lead
ranitidine (Glaxo)
(no imidazole at all) famotidine (Yamanouchi)
nizatidine (Eli Lilly)
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Case history #2: Suvorexant
Insomnia is a serious health problem
Orexin A and B are neuropeptides that regulate sleep
Orexins bind to a GPCR
Orexin antagonists could be sleep aids
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Merck identified a lead compound (3.89) from high throughput screening
Modification of the aromatic rings gave 3.90, 3.91, and finally 3.92
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3.92 has low bioavailability and undergoes rapid metabolism
SCHEME 3.3 Oxidative metabolism of the 1,4-diazepane ring of 3.92
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Further optimization
Methylation gave 3.95, which is resist to metabolism, but has low bioavailabilityFluorination and removal of a methyl group gave 3.96, which has better bioavailabilityAdding a benzoxazole in 3.97 reduces metabolism further, but has lower potencyAdding a chlorine increases potency, resulting in 3.98 (Suvorexant)
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An alternative orexin antagonist
More potent than suvorexant in vivo