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J Pharmacol Exp Ther. 1991 Nov;259(2):543-50.

Sigma compounds derived from phencyclidine: identification of PRE-084, a new, selective sigma ligand.

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National Institute on Drug Abuse Addiction Research Center, Baltimore, Maryland.


A series of compounds derived from phencyclidine (PCP) was examined in the sigma receptor and PCP receptor binding assays. The derivatives included compounds containing methylene, ethylene or carboxyl ethylene insertion between the cycloalkyl ring and the amine group of PCP. Various phenyl substitutions, cycloalkyl rings and amines of these derivatives were also examined. The methylene and ethylene insertions decreased the compounds' potencies at PCP receptors, whereas they increased the potencies at sigma receptors. The carboxyl ethylene insertion produced compounds with negligible potencies at PCP receptors while possessing high potencies for sigma receptors. One derivative (PRE-084; 2-(4-morpholino)ethyl 1-phenylcyclohexane-1-carboxylate hydrochloride) had an IC50 of 44 nM in the sigma receptor assay, an IC50 of more than 100,000 nM for PCP receptors and an IC50 higher than 10,000 nM in a variety of other receptor systems. In general, compounds with hydroxy-substituted phenyl groups tended to have decreased potency at sigma receptors, whereas methylphenyl and chlorophenyl substitutions increased potencies. Reduction of cycloalkyl ring size decreased potencies for sigma receptors and quaternized amine groups invariably lowered the compound's potencies. Conformational analysis indicated that PRE-084 fitted onto a pharmacophore model for the sigma ligands. The study describes a new, highly selective ligand for the sigma receptor. The results of this study also confirm distinctly different structural requirements for binding to sigma and PCP receptors and provide a new structural consideration for synthesizing sigma-selective compounds.

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