Synthesis of novel 3-substituted .beta.-carbolines as benzodiazepine receptor ligands: probing the benzodiazepine receptor pharmacophore

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Abstract
The 3-substituted .beta.-carbolines 2-4 and 5-7 were prepared from 3-amino-.beta.-carboline (8) in one step via diazotization, followed by reaction with the appropriate nucleophile in order to determine their bindng affinity for benzodiazepine receptors (BzR). All three of the 3-alkoxy-.beta.-carbolines 2 (IC50 = 124 nM), 3 (IC50 = 24 nM), and 4 (IC50 = 11 nM) have high affinities for BzR. The .beta.-carbolines substituted with electron-withdrawing groups including 5 (Cl; IC50 = 45 nM), 6 (NO2; IC50 = 125 nM), and 7 (N.dbd.C.dbd.S; IC50 = 8 nM) also had high affinities for BzR. The affinities of 5-8 clearly indicate that a carbonyl moiety at position 3 of a .beta.-carboline is not required for high-affinity binding to BzR. These findings have led to the development of a model for the binding of ligands to an inverse agonist domain at BzR. This model is supported by the recent synthesis of 3-ethoxy-.beta.-carboline (3), a potent, long-lived partial inverse agonist, and 7, an irreversible BzR ligand.

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