title: Discovery and synthesis of a new class of opioid ligand having a 3-azabicyclo[3.1.0]hexane core. An example of a 'magic methyl' giving a 35-fold improvement in binding.
abstract: In looking for a novel achiral μ opioid receptor antagonist for the treatment of pruritus, we designed and synthesised azabicyclo[3.1.0]hexane compounds as a new class of opioid ligand. During optimisation, an addition of a single methyl resulted in a 35-fold improvement in binding. An early example from the series had excellent μ opioid receptor antagonist antagonist activity and was very effective in an in vivo pruritus study.
authors: Pfizer Global Research and Development, Sandwich Laboratories, Sandwich, UK. graham.lunn@pfizer.com
authors: Graham
authors: G
authors: Lunn
authors: Bernard J
authors: BJ
authors: Banks
authors: Robert
authors: R
authors: Crook
authors: Neil
authors: N
authors: Feeder
authors: Alan
authors: A
authors: Pettman
authors: Yogesh
authors: Y
authors: Sabnis
mesh_terms: D000284:Administration, Oral; D000818:Animals; D053961:Azabicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D006586:Hexanes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D008024:Ligands; D011485:Protein Binding; D011537:Pruritus / Q000188:drug therapy; D051381:Rats; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D053961:Azabicyclo Compounds; D006586:Hexanes; D008024:Ligands; D017450:Receptors, Opioid, mu; D013449:Sulfonamides