Rigid Phencyclidine Analogues. Binding to the Phencyclidine and σ₁ Receptors

Abstract

Three phencyclidine (PCP) analogues possessing a highly rigid carbocyclic structure and an attached piperidine ring which is free to rotate were synthesized. Each analogue has a specific fixed orientation of the ammonium center of the piperidinium ring to the centrum of the phenyl ring. The binding affinities of the rigid analogues 1-piperidino-7,8-benzobicyclo[4.2.0]octene (14), 1-piperidinobenzobicyclo[2.2.1]heptene (16), and 1-piperidinobenzobicyclo[2.2.2]octene (13) for the PCP receptor ([3H]TCP) and σ-receptor (NANM) were determined. The three analogues show low to no affinity for the PCP receptor but good affinity for the σ-receptor and can be considered σ-receptor selective ligands with PCP/σ ratios of 13, 293, and 368, respectively. The binding affinities for the σ-receptor are rationalized in terms of a model for the σ-pharmacophore