Characteristics of the ligand-binding site interaction for a series of arecoline-derived muscarinic agonists: a quantum chemical study

This work focuses on electronic and conformational structure of bicyclic an alogues of arecoline and sulfoarecoline - muscarinic receptor agonists stru cturally related to 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol (THPO) a nd its S-methylsulfonium derivative (DHTO). Conformational freedom of six-m ember rings containing sulphur and nitrogen has been investigated by means of semiempirical AMI method. Interaction between 'cationic heads' of two re presentative compounds and HCO2- ion serving as a model of carboxyl group o f Asp in the muscarinic receptor has been modelled using DFT method in loca l approximation (LDA with VWN exchange-correlation functional). Electrostat ic potential (ESP) around studied complexes and ligands with added electron (simulation of complex formation) are presented and analysed. Position and depth of ESP minima in a series of studied ligands correlate well with the ir activity as muscarinic agonists. On the basis of our results the mechani sm of ligand-binding site interaction may be elucidated. The calculations a llow also for the comparison of bicyclic analogues of arecoline with alread y existing model for muscarinic pharmacophore and for rationalization of mo del parameters. (C) 2000 Elsevier Science Ltd. All rights reserved.