Molecular determinants for recognition of phencyclidine derivatives at muscarinic cholinergic receptors

Abstract

We report the results of a study combining synthetic organic chemistry, NMR spectroscopy, pharmacologic testing of receptor affinity, and theoretical calculations to elucidate the molecular determinants for the activity of phencyclidine (PCP) on the muscarinic type of acetylcholine receptor (M-ACh-R). A series of analogs was prepared to test the hypothesis that rigidity of the phenyl ring rotation and its relative orientation with respect to the cyclohexyl ring are responsible for PCP recognition at M-ACh-R. Quantum mechanical calculations (SCF with STO-3G basis sets) as well as molecular mechanics calculations (with the MM2 program) were used to elucidate the structures and define the conformations of the compounds, the rigidity of the phenyl ring arrangement, and the structural determinants for the recognition of these drugs at M-ACh-R. Pharmacologic testing indicates that there is no preference for an axial or equatorial configuration of the phenyl ring for interaction with M-ACh-R. This is consistent with the ACh-like interaction pharmacophore defined in earlier studies. However, the increased barrier to rotation of the phenyl ring in these compounds, compared to PCP, explains their increased affinity for M-ACh-R. A novel derivative in which the phenyl bisects the cyclohexyl ring rather than being perpendicular to it, as in the active PCP analogs, is not recognized at the M-ACh-R. Although it contains the same structural groups as PCP, we show that the stereochemistry of this derivative makes it incompatible with the ACh-like interaction pharmacophore.