1,2,4-Triazolyl azabicyclo[3.1.0]hexanes: a new series of potent and selective dopamine D(3) receptor antagonists

J Med Chem. 2010 Jan 14;53(1):374-91. doi: 10.1021/jm901319p.

Abstract

The discovery of new highly potent and selective dopamine (DA) D(3) receptor antagonists has recently allowed the characterization of the DA D(3) receptor in a range of preclinical animal models of drug addiction. A novel series of 1,2,4-triazol-3-yl-azabicyclo[3.1.0]hexanes, members of which showed a high affinity and selectivity for the DA D(3) receptor and excellent pharmacokinetic profiles, is reported here. Members of a group of derivatives from this series showed good oral bioavailability and brain penetration and very high in vitro affinity and selectivity for the DA D(3) receptor, as well as high in vitro potency for antagonism at this receptor. Several members of this series also significantly attenuate the expression of conditioned place preference (CPP) to nicotine and cocaine.

MeSH terms

  • Animals
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Computer Simulation
  • Drug Design
  • Guinea Pigs
  • Hexanes / chemistry*
  • Hexanes / pharmacology*
  • Humans
  • Male
  • Models, Animal
  • Models, Chemical
  • Molecular Structure
  • Receptors, Dopamine D3 / antagonists & inhibitors*
  • Receptors, Dopamine D3 / biosynthesis
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Hexanes
  • Receptors, Dopamine D3