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

T. P. Su, X. Z. Wu, E. J. Cone, K. Shukla, T. M. Gund, A. L. Dodge, D. W. Parish

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A series of compounds derived from phencyclidine (PCP) was examined in the σ 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 σ receptors. The carboxyl ethylene insertion produced compounds with negligible potencies at PCP receptors while possessing high potencies for σ receptors. One derivative (PRE-084; 2-(4-morpholino)ethyl 1-phenylcyclohexane-1- carboxylate hydrochloride) had an IC50 of 44 nM in the σ 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 σ receptors, whereas methylphenyl and chlorophenyl substitutions increased potencies. Reduction of cycloalkyl ring size decreased potencies for σ receptors and quaternized amine groups invariably lowered the compound's potencies. Conformational analysis indicated that PRE-084 fitted onto a pharmacophore model for the σ ligands. The study describes a new, highly selective ligand for the σ receptor. The results of this study also confirm distinctly different structural requirements for binding to σ and PCP receptors and provide a new structural consideration for synthesizing σ- selective compounds.

Original languageEnglish (US)
Pages (from-to)543-550
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number2
StatePublished - 1991
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology


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