The Organic Chemistry of Drug Design and Drug Action

1
The Organic Chemistry of Drug Design and Drug
Action

• Chapter 3
• Receptors

2

• 1878 Langley
• Study of antagonistic action of alkaloids on cat
  salivary flow suggests the compounds interacted
  with some substance in the nerve endings
• 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

3
Two fundamental characteristics of a receptor

• Recognition capacity - binding
• Amplification - initiation of response

4
Integral proteins embedded in phospholipid
bilayer of membranes
Figure 2.14
5
Drug-Receptor InteractionsPharmacodynamics
(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)
6
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)

7
Ionic Interaction

• Basic groups, e.g., His, Lys, Arg (cationic)
• Acidic groups, e.g., Asp, Glu (anionic)

Figure 3.1 ?G -5 kcal/mol
8
Ion-Dipole and Dipole-Dipole Interactions
?G -1 to -7 kcal/mol
Figure 3.2
9
Hydrogen Bonding

• Type of dipole-dipole interaction between H on
  X-H (X is an electronegative atom) and N, O, or F

?G -3 to -5 kcal/mol
Figure 3.3
10
3.5
a-helix
11
?-sheet
3.6
12
DNA
3.7
13
Charge-Transfer Complexes(molecular
dipole-dipole interaction)
chlorothalonil- fungicide
acceptor
donor
?G -1 to -7 kcal/mol
Figure 3.5
14
Hydrophobic Interactions
Increase in entropy of H2O molecules decreases
free energy. Therefore the complex is stabilized.
Figure 3.6
15
Hydrophobic Interaction
butamben - topical anesthetic
Figure 3.7
?G -0.7 kcal/mol per CH2/CH2 interaction
16
Van der Waals Forces
As molecules approach, temporary dipoles in one
molecule induce opposite dipoles in another
therefore, producing an intermolecular attraction
?G -0.5 kcal/mol per CH2/CH2 interaction
17
Figure 3.8
Dibucaine - local anesthetic
18
Dose-Response Curve
Muscle Contraction
Use any measure of response (LD50, ED50, etc.)
Figure 3.9
Means of measuring drug-receptor interactions
19
Full Agonist
Figure 3.10
20
Antagonists
Competitive Antagonist
Noncompetitive Antagonist
Different binding sites
Figure 3.11
21
Partial Agonist
low neurotransmitter added
agonist effect
high neurotransmitter added
antagonist effect
Figure 3.12
22
Inverse Agonists
full inverse agonist
Addition of an agonist or antagonist to an
inverse agonist (a, b, c are increasing
concentrations of agonist added)
partial inverse agonist
Figure 3.13
23

• 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

24
Two stages of drug-receptor interactions
1) complexation with receptor
2) initiation of response
(Stephenson) (Ariëns)
efficacy intrinsic activity
affinity
All are full agonists
5 different drugs ? 1 full agonist ? lt
1 partial agonists
Figure 3.15
25
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.
26
Table 3.1
Agonists - often structural similarity Antagonis
ts - little structural similarity
27
How can agonists and antagonists bind to same
site and one show response, other not?
Figure 3.14
agonist
antagonist
enantiomer

• All naturally-occurring chemicals in the body
  are agonists
• Most xenobiotics are antagonists
• Drugs that bind to multiple receptors ? side
  effects

28
Drug-Receptor Theories

• Occupancy Theory (1926)

29
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.
30
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 3.16
31
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 To
biological response
no biological response
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
32
Two-state (Multi-state) Receptor Model
R 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.
Figure 3.17
33
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 3.18
CH-O, N-, CH-
2 or 3 carbons
34
Drug and Receptor ChiralityDrug-Receptor
Complexes
Receptors are chiral (all L-amino acids) Racemic
mixture forms two diastereomeric complexes
DrugR DrugS ReceptorS
DrugR ReceptorS DrugS ReceptorS Have
different energies and stabilities
35
Chiral antihistamine
Kd 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
36
Distomer is really an impurity (isomeric
ballast)
May contribute to side effects and/or toxicity
3.13 (R)-()-thalidomide sedative/hypnotic
(S)-(-)-thalidomide teratogen
37
Enantiomers can have different activities
3.17 dextropropoxyphene (Darvon) analgesic
3.18 levopropoxyphene (Novrad) antitussive
(anticough)
38
Enantiomers can have opposite activities
barbiturate
S-()- convulsive
R-(-)- narcotic
(actually inverse agonists)
One enantiomer may antagonize the other with no
overall effect observed.
39
Stereoselectivity of one compound can vary for
different receptors
() - 3.23 butaclamol - antipsychotic (-) is
almost inactive
Eudismic ratio (/-) is 1250 for D2-dopaminergic,
160 for D1-dopaminergic, and 73 for ?-adrenergic
receptors
40
Hybrid drugs - different therapeutic activities
(-) - 3.25 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
41
Pseudo-hybrid drug - multiple isomeric forms
involved in biological activity
labetalol - antihypertensive
Figure 3.19
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)
42
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)
43
Single enantiomer drugs are expected to 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
44
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.
45
Receptor Interaction
Figure 3.20
Enantiomers cannot be distinguished with only two
binding sites.
46
Three-point attachment concept
Figure 3.21
Receptor needs at least three points of
interaction to distinguish enantiomers.
47
Geometric Isomers
The antihistamine activity of (E)-triprolidine
(3.35a) is 1000-fold greater than the (Z)-isomer.
48
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

49
Note that the bioactive conformation bound to the
peroxisome proliferator activated receptor gamma
(PPAR?) is not the lower energy extended
conformation.
Figure 3.22
50
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.
51
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.
52
Consider acetylcholine binding to muscarinic and
nicotine receptors
acetylcholine
53
Four conformers of acetylcholine (just staggered
conformers)
Lowest energy conformer
54
Conformationally rigid analogs
All exhibited low muscarinic receptor activity,
but 3.42a was most potent (0.06 times potency of
ACh).
55
To minimize the number of extra atoms, the
cyclopropane analog was made.
() - 3.45
The ()-trans isomer has about the same
muscarinic activity as acetylcholine (-)-trans
isomer 1/500th potency. Excellent support for the
anti-conformer as the bioactive conformer.
56
The only other isomer that can be made is the
cis-isomer (eclipsed).
(?)-cis isomer has negligible activity.
Therefore, acetylcholine binds to the muscarinic
receptor in an extended form (3.41a)
57
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).
58
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.
59
Possible conformers of piperidino ring
R
60
Conformationally Rigid Analogs
order of potency 3.50 gt 3.51 gt 3.49
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.
61
Ring Topology
chlorpromazine - tranquilizer
amitriptyline - antidepressant with a
tranquilizing side effect
imipramine - pure antidepressant
62
Figure 3.24
torsional angle
bending of ring planes
annellation angle of ring axes
tranquilizers - only ? mixed - ? and
? antidepressants - ?, ?, ?
You must consider the 3-dimensional structures of
rings.
63
Ion Channel Blockers
Calcium ion channel blockers prevent influx of
Ca which alters plateau phase of cardiac action
potential and therefore coronary blood flow.
Used for angina, arrhythmia, and hypertension
These three antihypertensive drugs bind to the
same Ca channel, but at different sites.
64
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
65
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
66
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.
67
Lead Discovery
Histamine analogs synthesized at Smith, Kline,
and French (now GlaxoSmithKline) Took four years
and 200 compounds 3.67 was very weakly active
(actually, partial agonist)
N?-guanylhistamine
68
Isosteric replacement
Isothiourea is more potent
69
Conformationally rigid analog(ring-chain
transformation)
Less potent therefore flexibility is important
Need to separate agonist and antagonist
properties - structures too similar to histamine.
70
imidazole retained for recognition
not charged
homolog
Had weak antagonistic activity without
stimulatory activity.
71
Homologation
further homologation
R CH3 burimamide purely competitive antagonist
for H2 receptor
Tested in humans - poor oral activity Could be
pharmacokinetics or pharmacodynamics
72
Consider pharmacodynamics
Imidazole ring can exist in 3 forms
Figure 3.25
73
Thioureido group can exist as 4 conformers
Side chain can be in many conformations Maybe
only a small fraction in the bioactive form
74
To increase potency of burimamide
Compare population of the imidazole form in
burimamide at physiological pH to that in
histamine.
75
Hammett Study of Electronic Effect of Side Chain
favored for R e- -withdrawing
favored for R e- -donating
pKa of imidazole 6.80 pKa of imidazole in
histamine 5.90 Therefore, side chain is e-
-withdrawing, favoring 3.72a.
pKa of imidazole in burimamide 7.25 Therefore,
side chain is e- -donating, favoring 3.72c.
Need to make side chain e- -withdrawing.
76
Isosteric replacement to lower the pKa of the
imidazole
A second way to increase population of 3.72a is
to put an e- -donating group at
4-position. metiamide (3.74, 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
77
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.
78
Metiamide 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.
79
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.
80
Linear free energy relationship between potency
and lipophilicity
cimetidine
Figure 3.27
81
Other H2 receptor antagonists made using
cimetidine as the lead
ranitidine (Glaxo) (no imidazole at all)
famotidine (Yamanouchi)