Fundamentals of Medicinal Chemistry

3.2.2 Conformation

Early work in the 1950s and early 1960s by Schueler and Archer suggested that

the flexibility of the structures of both ligands and receptors accounted for the

same ligand being able to bind to different sub-types of a receptor (see Appen-

dix 4). Archer also concluded that a ligand appeared to assume different

conformations when it bound to the different sub-types of a receptor. For

example, acetylcholine exhibits both muscarinic and nicotinic activity. Archer

et al. suggested that the muscarinic activity was due to theantior staggered

conformation, whilst the nicotinic activity was due to thesynor eclipsed form

(Figure 3.3).

The main methods of introducing conformational restrictions are by using

either bulky substituents, unsaturated structures or ring systems. Ring systems

are usually the most popular choice (Figure 3.4). In all cases, the structures used

must be chosen with care, because there will always be the possibility that steric

hindrance will prevent the binding of the analogue to the target. However, if

sufficient information is available, molecular modelling (see section 5.5) can be

of considerable assistance in the choice of structures.

3.2.3 Configuration

Configurational centres impose a rigid shape on sections of the molecule in

which they occur. However, their presence gives rise to geometric and optical

isomerism. Since these stereoisomers have different shapes, biologically active

stereoisomers will often exhibit differences in their potencies and/or activities

(Table 2.1). These pharmacological variations are particularly likely when a

chiral centre is located in a critical position in the structure of the molecule. The

consequence of these differences is that it is now necessary to make and test

separately all the individual stereoisomers of a drug.

Syn- acetylcholine Anti- acetylcholine

CH 3 COO

H H

N (CH 3 ) 3

H H

H OCOCH 3

H

H

H

C C

N+

CH 3

CH 3

CH 3

CH 3 COO

N (CH 3 ) 3

H HH HH

H

H

H

C

N+ OCOCH 3

CH 3
CH 3

CH 3

C

+

+

Figure 3.3 Synandanticonformers of acetylcholine and 2-tropanyl ethanoate methiodides

60 AN INTRODUCTION TO DRUG DISCOVERY