(2S)-1-(ARYLACETYL)-2-(AMINOMETHYL)PIPERIDINE DERIVATIVES - NOVEL, HIGHLY SELECTIVE KAPPA-OPIOID ANALGESICS

This paper describes the synthesis and structure-activity relationships as kappa-opoid analgesics of a novel class of 1-(arylacetyl)-2-(aminomethyl)piperidine derivatives (8). The active conformation of the pharmacophore, with a torsional angle (N1C2C7N8) of 60-degrees, was defined with computational studies and H-1 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 (14) and (2S)-1-[[4-(trifluromethyl)phenyl]acetyl]-2-(pyrrolidin-1-ylmethyl)piperidine hydrochloride (21) are the most kappa/mu selective (respectively 6500:1 and 4100:1) and among the most potent (K(i)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.