title: Identification and characterization of a novel class of atypical dopamine receptor agonists.
abstract: OBJECTIVE
  The D3 dopamine receptor exhibits tolerance and slow response termination (SRT) properties that are not exhibited by the closely-related D2 dopamine receptor. We previously demonstrated that the induction of tolerance elicits a unique conformational change in the D3 receptor. Here we tested the hypothesis that the tolerance and SRT properties of the D3 receptor are ligand-dependent.
  
  
  METHODS
  We used pharmacophore modeling and in silico screening approaches coupled with electrophysiological and biochemical methods to identify and functionally characterize the novel dopamine receptor agonists.
  
  
  RESULTS
  We identified cis-8-OH-PBZI (PBZI), FAUC73 and an additional novel compound, ES609, which although they are full D3 receptor agonists, do not induce the tolerance and SRT properties of the D3 receptor. In addition, PBZI has full intrinsic activity at D2L, is a partial agonist at D2S and exhibits functional selectivity at D4.2 dopamine receptors. ES609 is a partial agonist at D2S, D2L and D4.2 receptors, and exhibits functional selectivity at D2L and D4.2 dopamine receptors.
  
  
  CONCLUSIONS
  We have discovered a novel class of atypical dopamine receptor agonists that include three structurally dissimilar compounds. These new agonists will help determine the physiological and pathophysiological relevance of D3 receptor tolerance and SRT properties.
authors.affiliation: Department of Pharmacology & Physiology, UMDNJ-New Jersey Medical School, MSB, I-647, 185 South Orange Avenue, Newark, New Jersey 07103, USA. kuzhikev@umdnj.edu
authors.forename: E V
authors.initials: EV
authors.lastname: Kuzhikandathil
authors.forename: S
authors.initials: S
authors.lastname: Kortagere
mesh_terms: D000818:Animals; D002082:Butylamines / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D018491:Dopamine Agonists / Q000737:chemistry* / Q000494:pharmacology*; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation; D011954:Receptors, Dopamine / Q000737:chemistry / Q000378:metabolism*
chemical_list: C000593232:4-(2-chlorophenyl)butan-2-amine; D002082:Butylamines; D018491:Dopamine Agonists; D011954:Receptors, Dopamine