β-Carbolines: Synthesis and neurochemical and pharmacological actions on brain benzodiazepine receptors

Michael Cain, Robert W. Weber, Fil Guzman, James M. Cook, Steven A. Barker, Kenner C. Rice, Jacqueline Crawley, Steven M. Paul, Phil Skolnick

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Abstract

We have prepared a series of tetrahydro-β-carbolines (THβC), β-carbolines (β-C), and other nitrogen heterocycles and evaluated them in vitro with respect to their ability to bind to benzodiazepine receptors. The fully aromatic β-C's were more potent than their corresponding THβC derivatives. When substituents possessing a carbonyl (CO2Me, COCH3, CHO) were introduced at the β-C 3-position the in vitro potency was augmented. Alcohol substituents (CH2OH, CHOHCH3) demonstrated decreased in vitro potency. The importance of the carbonyl moiety was further demonstrated when β-carboline-3-carboxylic acid was shown to bind tighter to benzodiazepine receptors at lower pH. A lower pH increases the concentration of the acid and decreases the concentration of the anion. 3-(Hydroxymethyl)-β-carboline (24), 3-formyl-β-carboline (25) and 3-acetyl-β-carboline (27) were benzodiazepine antagonists in vivo. Methyl isoquinoline-3-carboxylate (31a) also had in vitro activity. The same structure-activity relationships seen in β-C's were also observed for isoquinolines.

Original languageEnglish (US)
Pages (from-to)1081-1091
Number of pages11
JournalJournal of Medicinal Chemistry
Volume25
Issue number9
StatePublished - 1982
Externally publishedYes

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ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Cain, M., Weber, R. W., Guzman, F., Cook, J. M., Barker, S. A., Rice, K. C., Crawley, J., Paul, S. M., & Skolnick, P. (1982). β-Carbolines: Synthesis and neurochemical and pharmacological actions on brain benzodiazepine receptors. Journal of Medicinal Chemistry, 25(9), 1081-1091.