Design of an irreversible affinity ligand for the phencyclidine recognition site on N-methyl-D-aspartate-type glutamate receptors

S. O. Casalotti, A. P. Kozikowski, A. Fauq, W. Tuckmantel, K. E. Krueger

Research output: Contribution to journalArticle


A series of 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP) analogs were synthesized with the aim of developing a potent ligand for the N-methyl-D- aspartate glutamate receptor subtype. The piperidine moiety of TCP was substituted at the nitrogen position with aliphatic chains of different length or with various polar groups. A correlation between the decrease in the potency of displacement of [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo- [a,d]cyclohepten-5,10-imine maleate (MK-801) binding from bovine cortex membranes and the increase of length or polarity of the aliphatic chain was observed. Isonitrile, isothiocyanate and isoselenocyanate groups were substituted at position 4 of the thiophene ring, and the relative binding affinity and alkylating potencies of the derivatized compounds were studied. Among this set of compounds, the one carrying an isothiocyanate group at position 4 of the thiophene ring of the N-ethyl analog of TCP yielded the most efficient alkylating agent, demonstrated by its ability to irreversibly block up to 80% of the [3H]MK-801 binding sites. This affinity ligand did not significantly affect other ligand binding sites of the same N-methyl-D- aspartate receptor complex or of other receptor systems, further demonstrating its functional specificity as a potent alkylating probe for the TCP/MK-801 recognition site. Studies with a radiolabeled adduct of this isothiocyanate N-ethyl derivative, however, indicate that a substantial level of nonspecific covalent incorporation into the membranes occurs at concentrations as low as 10 nM, thereby obscuring any possibility of detecting a specifically labeled protein species.

Original languageEnglish (US)
Pages (from-to)21-28
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number1
StatePublished - Jan 1 1992


ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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