Structural requirements for agonist actions at the benzodiazepine receptor: studies with analogues of 6-(benzyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester.

The analogues 2, 3, 8a-c, 9, 13, and 14 of the beta-carboline 6-(benzyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester (ZK-93423, 1) were synthesized in order to determine which functional groups are required for agonist activity exhibited by the parent compound 1 at the benzodiazepine receptor (BzR). The potencies of these compounds were evaluated in vitro and in vivo; the beta-carbolines 2, 8a-c, and 13 were found to exhibit high affinity (0.5-22 nM) for BzR, but in vivo studies demonstrated they were not anticonvulsant while analogues 8a and 8b antagonized the effects of diazepam. These results are in agreement with the model proposed for the pharmacophore of the agonist site (domain) of the BzR, which requires the interaction of two sites of electron density [N(2) and C(4)], a third at E+ (electrostatic or steric), and two of lipophilicity [C(3) and C(6)] of the ligand with the BzR protein (see Figure 1). The pharmacophore for the agonist site is derived from the structure-activity relationships of the benzodiazepines, pyrazoloquinolines, and the beta-carboline 1, and compared to interactions required for ligand inverse agonist activity.