Selective 5-hydroxytryptamine 2c receptor agonists derived from the lead compound tranylcypromine: Identification of drugs with antidepressant-like action

Jin Cho Sung, Niels H. Jensen, Toru Kurome, Sudhakar Kadari, Michael L. Manzano, Jessica E. Malberg, Barbara Caldarone, Bryan L. Roth, Alan P. Kozikowski

Research output: Contribution to journalArticle

Abstract

We report here the design, synthesis, and pharmacological properties of a series of compounds related to tranylcypromine (9), which itself was discovered as a lead compound in a high-throughput screening campaign. Starting from 9, which shows modest activity as a 5-HT 2C agonist, a series of 1-aminomethyl-2- phenylcyclopropanes was investigated as 5-HT 2C agonists through iterative structural modifications. Key pharmacophore feature of this new class of ligands is a 2-aminomethyl-trans-cyclopropyl side chain attached to a substituted be zene ring. Among the tested compounds, several were potent and efficacious 5-HT 2C receptor agonists with selectivity over both 5-HT 2A and 5-HT2B receptors in functional assays. The most promising compound is 37, with 120- and 14-fold selectivity over 5-HT 2A and 5-HT 2B, respectively (EC 50) 585, 65, and 4.8 nM at the 2A, 2B, and 2C subtypes, respectively). In animal studies, compound 37 (10-60 mg/kg) decreased immobility time in the mouse forced swim test.

Original languageEnglish (US)
Pages (from-to)1885-1902
Number of pages18
JournalJournal of medicinal chemistry
Volume52
Issue number7
DOIs
StatePublished - Apr 9 2009

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Sung, J. C., Jensen, N. H., Kurome, T., Kadari, S., Manzano, M. L., Malberg, J. E., Caldarone, B., Roth, B. L., & Kozikowski, A. P. (2009). Selective 5-hydroxytryptamine 2c receptor agonists derived from the lead compound tranylcypromine: Identification of drugs with antidepressant-like action. Journal of medicinal chemistry, 52(7), 1885-1902. https://doi.org/10.1021/jm801354e