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

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

Abstract

A series of 3,6-disubstituted β-carbolines was synthesized and evaluated for their in vitro affinities at α(x)β(3)γ(2) GABA(A)/benzodiazepine receptor subtypes by radioligand binding assays in search of α(1) subtype selective ligands to treat alcohol abuse. Analogues of β-carboline-3-carboxylate-t-butyl ester (βCCt, 1) were synthesized via a CDI-mediated process and the related 6-substituted β-carboline-3-carboxylates 6 including WYS8 (7) were synthesized via a Sonogashira or Stille coupling processes from 6-iodo-βCCt (5). The bivalent ligands of βCCt (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 β-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 β-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 β-carboline ligands (βCCt, 3PBC and WYS8), which preferentially bound to α1 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 β-carbolines were 'near GABA neutral antagonists'. Based on the SAR, the most potent (in vitro) α(1) selective ligand was the 6-substituted acetylenyl βCCt (WYS8, 7). Earlier both βCCt 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 β-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 β-carbolines presented here.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcoholism / drug therapy*
  • Animals
  • Benzodiazepines / chemistry*
  • Binding Sites
  • Carbolines / chemical synthesis
  • Carbolines / chemistry*
  • Carbolines / therapeutic use
  • Cell Line
  • Computer Simulation
  • GABA-A Receptor Antagonists / chemical synthesis*
  • GABA-A Receptor Antagonists / chemistry
  • GABA-A Receptor Antagonists / therapeutic use
  • Humans
  • Protein Subunits / antagonists & inhibitors
  • Protein Subunits / metabolism
  • Rats
  • Receptors, GABA-A / chemistry*
  • Receptors, GABA-A / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • 8-ethynyl-beta-carboline-3-carboxylate-t-butyl ester
  • Carbolines
  • GABA-A Receptor Antagonists
  • Protein Subunits
  • Receptors, GABA-A
  • Benzodiazepines