Structural features controlling the binding of beta-carbolines to the benzodiazepine receptor.

Beta-carbolines are a class of drug which can interact with a high affinity with the benzodiazepine (BDZ) binding site of the GABAA receptor. The present paper, aimed at obtaining a deeper insight into the structure-properties relationships of this class of molecules, reports the crystal structures of four beta-carbolines: ZK93423 (3-carboethoxy-4-methoxymethyl-6-benzyloxy-beta-carboline), ZK91296 (3-carboethoxy-4-methoxymethyl-5-benzyloxy-beta-carboline), FG7142 (N-methyl-3-carbamoyl-beta-carboline) and the low-affinity ligand harmine hydrochloride (1-methyl-7-methoxy-beta-carboline). This set of structural data is completed by the X-ray structures of other carbolines of known biological activity retrieved from the Cambridge Crystallographic Database and by the structures of beta-CCE (3-carboethoxy-beta-carboline), 6-PBC (3-carboethoxy-4-methoxymethyl-6-isopropoxy-beta-carboline), PRCC (3-isopropoxy-beta-carboline) and ZK93426 (3-carboethoxy-4-methyl-5-isopropoxy-beta-carboline), which have been obtained by molecular-mechanics simulations. The structural features of all these molecules have been compared according to the stereochemical model we proposed in 1987. The structural comparison is integrated by the Free-Wilson analysis on 32 beta-carbolines of known binding affinity data.