title: (2S)-1-(arylacetyl)-2-(aminomethyl)piperidine derivatives: novel, highly selective kappa opioid analgesics.
abstract: This paper describes the synthesis and structure-activity relationships as kappa opioid analgesics of a novel class of 1-(arylacetyl)-2-(aminomethyl)piperidine derivatives. The active conformation of the pharmacophore, with a torsional angle (N1C2C7N8) of 60 degrees, was defined with computational studies and 1H NMR. A quantitative structure-activity relationship study of the arylacetic moiety substitution indicated that the presence of an electron-withdrawing and lipophilic substituent in para and/or meta positions is required for good analgesic activity and kappa affinity. The lead compounds (2S)-1-[(3,4-dichlorophenyl)acetyl]-2-(pyrrolidin-1-ylmethyl )piperidine hydrochloride and (2S)-1-[4-(trifluoromethyl)phenyl]acetyl]-2-(pyrrolidin-1-ylmet hyl) piperidine hydrochloride are the most kappa/mu selective (respectively 6500:1 and 4100:1) and among the most potent (Ki kappa 0.24 and 0.57 nM, respectively) kappa ligands identified so far. In the mouse tail flick model of antinociception, compound 14 (ED50 = 0.05 mg/kg sc) was 25 times more potent than morphine and 16 times more potent than the standard kappa ligand U-50488.
authors.affiliation: Zambeletti Research Laboratories, Baranzate, Milan, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Vecchietti
authors.forename: A
authors.initials: A
authors.lastname: Giordani
authors.forename: G
authors.initials: G
authors.lastname: Giardina
authors.forename: R
authors.initials: R
authors.lastname: Colle
authors.forename: G D
authors.initials: GD
authors.lastname: Clarke
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis*; D000818:Animals; D001921:Brain / Q000378:metabolism; D006168:Guinea Pigs; D007202:Indicators and Reagents; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011957:Receptors, Opioid / Q000187:drug effects* / Q000378:metabolism; D017473:Receptors, Opioid, kappa; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D007202:Indicators and Reagents; D010880:Piperidines; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa