Bridged γ-Carbolines and Derivatives Possessing Selective and Combined Affinity for 5-HT2 and D2 Receptors

Richard E. Mewshaw, Lisa S. Silverman, Rose M. Mathew, Carl Kaiser, Ronald G. Sherrill, Menyan Cheng, Carol W. Tiffany, E. William Karbon, Michael A. Bailey, Susan A. Borosky, John W. Ferkany, Mary E. Abreu

Research output: Contribution to journalArticle

Abstract

A series of 5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indoles and 6,7,8,9,10,11-hexahydro-7,-11-imino-5H-cyclooct[b]indoles was prepared. Structural modifications of the lead compound, 11-[4-(4-fluorobenzoyl)propyl]-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole (5, Ki = 0.82 nM vs [3H]ketanserin) enabled the identification of the functionality necessary for high affinity at serotonin 5-HT2 and dopamine D2 receptors in ligand binding studies. The indole ring, as well as the benzoyl or isosteric benzisoxazole moiety, were essential for high affinity. Variations of the length of the side chains resulted in ligands having either selective affinity for the 5-HT2 receptor or a combination of 5-HT2 and D2 affinity. In vivo binding studies were performed on selected members in this series. The most potent member, 2-fluoro-11-[4-(4-fluorobenzoyl)butyl]-5,6,7,8,9,-10-hexahydro-7,10-iminocyclohept[b]indole (36) had an ED50 of <1 mg/kg at the 5-HT2 and D2 receptors following oral administration.

Original languageEnglish (US)
Pages (from-to)1488-1495
Number of pages8
JournalJournal of medicinal chemistry
Volume36
Issue number10
DOIs
StatePublished - Jan 1 1993

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Mewshaw, R. E., Silverman, L. S., Mathew, R. M., Kaiser, C., Sherrill, R. G., Cheng, M., Tiffany, C. W., Karbon, E. W., Bailey, M. A., Borosky, S. A., Ferkany, J. W., & Abreu, M. E. (1993). Bridged γ-Carbolines and Derivatives Possessing Selective and Combined Affinity for 5-HT2 and D2 Receptors. Journal of medicinal chemistry, 36(10), 1488-1495. https://doi.org/10.1021/jm00062a023