Novel 1-Phenylcycloalkanecarboxylic Acid Derivatives Are Potent and Selective σ1 Ligands

Silvia N. Calderon, Sari Izenwasser, Brett Heller, J. Silvio Gutkind, Mariena V. Mattson, Tsung Ping Su, Amy Hauck Newman

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Carbetapentane (1, 2-[2-(diethylamino)ethoxy]ethyl 1-phenyl-1-cyclopentanecarboxylate) binds with high affinity to σ sites and is a potent antitussive, anticonvulsant, and spasmolytic agent. However, carbetapentane interacts at muscarinic binding sites as well, and it is not clear whether either of these receptor systems is involved in the mechanism(s) of action(s) of this drug. In an attempt to determine whether these psychoactivities can be attributed to interaction at σ sites, a series of carbetapentane analogs were prepared. Phenyl ring substitution; contraction, expansion, and replacement with a methyl group of the cyclopentyl ring; replacement of the carboxylate function with an amide, methyl ether, and methylamine; and replacement of the N,N-diethyl substituent with a morpholino or piperidino moiety were investigated. All of these novel analogs were evaluated for binding to σ1 and σ2 sites, and comparison of binding at muscarinic m1 and m2 and PCP (1-(1-phenylcyclohexyl)piperidine) receptors was performed. All of the compounds were selective for σ1 over σ2 sites, with the three most selective analogs being compounds 34 (65-fold), 35 (78-fold), and 39 (51-fold). None of the compounds were active at PCP sites, and chemical modification including (1) replacing the ester function, (2) replacing the cyclopentyl ring with a smaller ring system (cyclopropyl) or a methyl group, and (3) replacing the diethylamino moiety with a morpholino group resulted in > 220-fold selectivity over muscarinic receptor binding. Therefore, several of these novel compounds are potent, σ1-selective ligands which can now be investigated as potential antitussive, anticonvulsant, and antiischemic agents. These studies may reveal whether σ1 sites play a role in the pharmacological actions of these drugs.

Original languageEnglish (US)
Pages (from-to)2285-2291
Number of pages7
JournalJournal of Medicinal Chemistry
Volume37
Issue number15
DOIs
StatePublished - Jul 1 1994
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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