Design, synthesis, and subtype selectivity of 3,6-disubstituted β-carbolines at Bz/GABA(A)ergic receptors. SAR and studies directed toward agents for treatment of alcohol abuse

A series of 3,6-disubstituted beta-carbolines was synthesized and evaluated for their in vitro affinities at alpha(x)beta(3)gamma(2) GABA(A)/benzodiazepine receptor subtypes by radioligand binding assays in search of alpha(1) subtype selective ligands to treat alcohol abuse. Analogues of beta-carboline-3-carboxylate-t-butyl ester (beta CCt, 1) were synthesized via a CDI-mediated process and the related 6-substituted beta-carboline-3-carboxylates 6 including WYS8 (7) were synthesized via a Sonogashira or Stille coupling processes from 6-iodo-beta CCt (5). The bivalent ligands of bCCt (32 and 33) were also designed and prepared via a palladium-catalyzed homocoupling process to expand the structure-activity relationships (SAR) to larger ligands. Based on the pharmacophore/receptor model, a preliminary SAR study on 34 analogues illustrated that large substituents at position-6 of the b-carbolines were well tolerated. As expected, these groups are proposed to project into the extracellular domain (L-Di region) of GABA(A)/Bz receptors (see 32 and 33). Moreover, substituents located at position-3 of the beta-carboline nucleus exhibited a conserved stereo interaction in lipophilic pocket L-1, while N(2) presumably underwent a hydrogen bonding interaction with H-1. Three novel b-carboline ligands (bCCt, 3PBC and WYS8), which preferentially bound to alpha 1 BzR subtypes permitted a comparison of the pharmacological efficacies with a range of classical BzR antagonists (flumazenil, ZK93426) from several different structural groups and indicated these b-carbolines were 'near GABA neutral antagonists'. Based on the SAR, the most potent (in vitro) a1 selective ligand was the 6-substituted acetylenyl bCCt (WYS8, 7). Earlier both bCCt and 3PBC had been shown to reduce alcohol self-administration in alcohol preferring (P) and high alcohol drinking (HAD) rats but had little or no effect on sucrose self-administration. 1-3 Moreover, these two b-carbolines were orally active, and in addition, were anxiolytic in P rats but were only weakly anxiolytic in rodents. These data prompted the synthesis of the bcarbolines presented here. Published by Elsevier Ltd.