3-Pyrroline containing arylacetamides: A novel series of remarkably selective κ-agonists

A series of 2-(substituted phenyl)-N-methyl-N-[(1S)-1-(substituted alkyl)-2-(1-(3-pyrrolinyl))ethyl]acetamides were synthesized and evaluated as highly selective kappa-agonists with Ki values in low nanomolar range. 3-Pyrroline incorporated into the basic amino functionality in combination with 2-(methylthio)ethyl substituent on the carbon adjacent to the amide nitrogen remarkably enhanced the κ-selectivity. 3,4-Dichlorophenyl derivative 1e was found the most potent and selective analgesic in this series with ED50 value of 0.023 mg/kg.