Fluoromethylated and Hydroxymethylated Derivatives of N-Methyl-D-aspartate Receptor Antagonist 1[1-(2-Thienyl)cyclohexyl]piperidine

Abstract

Derivatives with fluoromethyl and hydroxymethyl groups on the cyclohexyl ring of 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP), a noncompetitive antagonist of N-methyl-D-aspatrate (NMDA) receptor, were tested in a radioligand binding assay to evaluate their ability to inhibit [³H]TCP binding by rat brain homogenates. The potencies of these compounds as antagonists of NMDA and L-glutamate responses were also compared using a rat cortical slice preparation.One of the analogs, cis-2-hydroxymethyl-r-1-(N-piperidyl)-1-(2-thienyl)cyclohexane (5) was found to show a high affinity (IC₅₀=16 nM) for the phencyclidine (PCP) binding sites, very close to that of TCP, and to be 38-fold more potent in binding than its trans isomer. Fluoromethyl and hydroxymethyl substitutions at C₄ position of the cyclohexyl ring of TCP clearly reduced the affinity by at least one order of magnitude relative to TCP.