β-Carbolines: Synthesis and Neurochemical and Pharmacological Actions on Brain Benzodiazepine Receptors

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.