.beta.-Carbolines: synthesis and neurochemical and pharmacological actions on brain benzodiazepine receptors

Abstract

A series of tetrahydro-.beta.-carbolines (TH.beta.C), .beta.-carbolines (.beta.-C), and other N heterocycles were synthesized and evaluated in vitro for their ability to bind to benzodiazepine receptors. The fully aromatic .beta.-C were more potent than their corresponding TH.beta.C derivatives. When substituents possessing a carbonyl (CO2Me, COCH3, CHO) were introduced at the .beta.-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 .beta.-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)-.beta.-carboline, 3-formyl-.beta.-carboline and 3-acetyl-.beta.-carboline were benzodiazepine antagonists in vivo. Methyl isoquinoline-3-carboxylate also had in vitro activity. The same structure-activity relationships seen in .beta.-C were also observed for isoquinolines.