3-Pyrroline containing arylacetamides: a novel series of remarkably selective kappa-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 K(i) 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 kappa-selectivity. 3,4-Dichlorophenyl derivative 1e was found the most potent and selective analgesic in this series with ED(50) value of 0.023 mg/kg.
Mou
Qi-Yong
QY
Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Chen
Jie
J
Zhu
You-Cheng
YC
Zhou
De-He
DH
Chi
Zhi-Qiang
ZQ
Long
Ya-Qiu
YQ
D000081:Acetamides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D006801:Humans; D007274:Injections, Intraperitoneal; D010146:Pain / Q000188:drug therapy; D011758:Pyrroles / Q000737:chemistry; D011869:Radioligand Assay; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D013329:Structure-Activity Relationship
D000081:Acetamides; D000701:Analgesics, Opioid; D011758:Pyrroles; D017473:Receptors, Opioid, kappa; C013231:pyrroline