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

Article Details

Citation

Yin W, Majumder S, Clayton T, Petrou S, VanLinn ML, Namjoshi OA, Ma C, Cromer BA, Roth BL, Platt DM, Cook JM

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

Bioorg Med Chem. 2010 Nov 1;18(21):7548-64. doi: 10.1016/j.bmc.2010.08.049. Epub 2010 Sep 29.

PubMed ID
20888240 [ View in PubMed
]
Abstract

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 (betaCCt, 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-betaCCt (5). The bivalent ligands of betaCCt (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 beta-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 beta-carboline ligands (betaCCt, 3PBC and WYS8), which preferentially bound to alpha1 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 beta-carbolines were 'near GABA neutral antagonists'. Based on the SAR, the most potent (in vitro) alpha(1) selective ligand was the 6-substituted acetylenyl betaCCt (WYS8, 7). Earlier both betaCCt 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 beta-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 beta-carbolines presented here.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
ZolpidemGamma-aminobutyric acid receptor subunit alpha-1Ki (nM)26.7N/AN/ADetails
ZolpidemGamma-aminobutyric acid receptor subunit gamma-2Ki (nM)156N/AN/ADetails
ZolpidemGamma-aminobutyric acid receptor subunit gamma-2Ki (nM)383N/AN/ADetails
ZolpidemGamma-aminobutyric acid receptor subunit gamma-2Ki (nM)>10000N/AN/ADetails