The search for TCP analogues binding to the low affinity PCP receptor sites in the rat cerebellum

With the aim of obtaining selective ligands of the low affinity binding sites of [3H]-1-[1-(2-thienyl)cyclohexyl]piperidine ([3H]TCP) in the rat cerebellum, oxygen and sulfur atoms were introduced in the TCP structure and derivatives to obtain analogues with a lowered lipophilicity. These compounds, and others already obtained, were assayed comparatively to determine their affinities for three sites labeled with [3H]TCP: one in the forebrain, the originally described PCP receptor, and two in the rat cerebellum. Lowering the lipophilicity and modifying the hetero-aromatic moiety yielded some ligands with increased affinity for the low affinity sites in the rat cerebellum and decreased affinity for the high affinity sites in the forebrain. Particularly, two compounds displaying both a high affinity and a good selectivity might be valuable tools to elucidate the pharmacology of the low affinity PCP sites labeled with [3H]TCP in the rat cerebellum.