Fundamentals of Medicinal Chemistry

new agonists is usually the structure of the endogenous ligand or its pharmaco-

phore. This information is normally obtained from a study of the binding of the

endogenous ligand to the receptor using X-ray crystallography, nuclear mag-

netic resonance (NMR) and computerized molecular modelling techniques.

However, it is emphasized that many agonists have structures that are not

directly similar to those of their endogenous ligands.

A common approach to designing new drugs that act on a receptor is to synthe-

size and investigate the activity of a series of compounds with similar structures to

that of either compounds that are known to bind to the receptor, the endogenous

ligand or the pharmacophoreof the endogenous ligand(Table 7.4). This approach

isanexampleoftheuseofSARdiscussedinchapter4.Itisbasedontheassumption

that a new agonist is more likely to be effective if its structure contains the same

binding groups and bears some resemblance to the endogenous ligand.

The binding groups are not the only consideration when designing a drug to

act at a receptor; the drug must also be of the correct size and shape to bind to

and activate the receptor. Once again, the initial approach is to use the structure

of the endogenous ligand or other active compounds as models. If sufficient

data is available to construct a computer model of the receptor, the docking

procedure (see section 5.5) may be used to check whether a lead or its analogues

is likely to be able to bind to that receptor. Information concerning the best

shape for a new agonist may also be obtained from a study of the conformations

and configurations of a number of active analogues of the endogenous ligand.

7.4.2 Antagonists

Antagonists are ligands that inhibit the action of an agonist. Their are classified

as eithercompetitiveornon-competitive. Competitive antagonists bind to the

Table 7.4 A series of compounds typical of that used in a search for a new agonist for the neurotransmitter

acetylcholine. The activity is given in terms of the molar ratio needed to give the same degree of potency as

acetylcholine

Structure

Activity

Structure

Activity

Cat blood

pressure

Frog

heart

Cat blood

pressure

Frog

heart

CH 3 COOCH 2 CH 2 N

þ

(CH 3 ) 3

Acetylcholine

11CH 3 COOCH 2 CH 2 N

þ

H(CH 3 ) 2 50 50

CH 3 COOCH 2 CH 2 N

þ

H 2 CH 3 500 500 CH 3 COOCH 2 CH 2 N

þ

H 3 2000 40 000

CH 3 COOCH 2 CH 2 N

þ

(C 2 H 5 ) 3 2000 10 000 CH 3 COOCH 2 CH 2 P

þ

(CH 3 ) 3 13 12

CH 3 COOCH 2 CH 2 S

þ

(CH 3 ) 2 50 96

DRUGS THAT TARGET RECEPTORS 145