(2S)-1-(arylacetyl)-2-(aminomethyl)piperidine derivatives: novel, highly selective kappa opioid analgesics.
Article Details
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Vecchietti V, Giordani A, Giardina G, Colle R, Clarke GD
(2S)-1-(arylacetyl)-2-(aminomethyl)piperidine derivatives: novel, highly selective kappa opioid analgesics.
J Med Chem. 1991 Jan;34(1):397-403.
- PubMed ID
- 1846921 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Morphine Kappa-type opioid receptor Ki (nM) 151 N/A N/A Details Morphine Mu-type opioid receptor Ki (nM) 3.3 N/A N/A Details