6533b839fe1ef96bd12a637c

RESEARCH PRODUCT

Conformational Isomerism in Drug Action: Does the Free Energy of Binding Induce the Pharmacophoric Conformation of Semi-Rigid Muscarinic Agonists?

subject

description

The physiological neurotransmitter Acetylcholine has been shown to have great molecular flexibility, and because of this, the possibility of forming numerous energetically different conformations. This property makes the determination of the biologically active conformation extremely complicated. In attempts to solve this problem various research groups have tried two basically different approaches: (1) (1) The determination of the energetically most stable conformation using crystallographic methods (X-ray diffraction studies), nuclear magnetic resonance and quantum-mechanical calculations [1–16]. Same workers hypothesized that the energetically most favourable form was also the biologically most active conformation [17,18]. (2) The synthesis and pharmacological testing of Acetylcholine analogues with rigid or semi-rigid structure. The synthetic compounds showing high activities enable an indirect indication as to the active conformation of Acetylcholine [19–28].