Michael L. Sabio

Recognition of cholinergic agonists by the muscarinic receptor. 1. Acetylcholine and other agonists with the NCCOCC backbone.

A theoretical model is used to deduce the pharmacologically active conformation of acetylcholine and other agonists interacting with the muscarinic receptor of the parasympathetic and central nervous systems. This is accomplished by replacing the usual dihedral angles tau 1 and tau 2, which define the conformations of cholinergic drugs, with two new geometric parameters more suitable for describing the muscarinic pharmacophore: a characteristic distance, [PQ], and a dihedral angle, PNOQ. Values for these parameters are determined by conformational analysis on semirigid muscarinic agonists using molecular mechanics and ab initio molecular orbital methods. In addition to deducing the active conformation of acetylcholine and other agonists, the model also rationalizes the pattern of stereoselectivity in agonists related to 3-acetoxyquinuclidine (aceclidine) and furnishes a geometric criterion for partial agonism and antagonism.

Borepin and its valence isomers

Ab initio calculations show borepin to be planar and more stable than its valence isomers boranorbornadiene and boranorcaradiene by a considerable amount; the latter have Cs symmetry.