title: Structure/activity studies related to 2-(3,4-dichlorophenyl)-N-methyl-N-[2-(1-pyrrolidinyl)-1-substituted- ethyl]acetamides: a novel series of potent and selective kappa-opioid agonists.
abstract: This paper describes the synthesis of a series of N-[2-(1-pyrrolidinyl)ethyl]acetamides 1, variously substituted at the carbon adjacent to the amide nitrogen (C1), and related analogues, together with their biological evaluation as opioid kappa agonists. In the first part of the study, the variants in N-acyl, N-alkyl, and amino functions were explored when the substituent at C1 was 1-methylethyl and the optimum was found to be exemplified by 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1-(1-methylethyl)-2- (1-pyrrolidinyl)ethyl]acetamide (13). Subsequently, racemic or chiral amino acids were used to introduce other alkyl and aryl substituents at C1 of the ethyl linking moiety. A series of potent compounds, bearing substituted-aryl groups at C1, were discovered, typified by 2-(3,4-dichloro-phenyl)-N-methyl-N-[(1R,S)-1-(3-aminophenyl)-2-(1- pyrrolidinyl)ethyl]acetamide (48), which was 5-fold more active as the racemate than 13 in vitro and exhibited potent naloxone-reversible analgesic effects (ED50 = 0.04 mg/kg sc) in a mouse abdominal constriction model.
authors.affiliation: Research Department, ICI Pharmaceuticals, Macclesfield, Cheshire, England.
authors.forename: J J
authors.initials: JJ
authors.lastname: Barlow
authors.forename: T P
authors.initials: TP
authors.lastname: Blackburn
authors.forename: G F
authors.initials: GF
authors.lastname: Costello
authors.forename: R
authors.initials: R
authors.lastname: James
authors.forename: D J
authors.initials: DJ
authors.lastname: Le Count
authors.forename: B G
authors.initials: BG
authors.lastname: Main
authors.forename: R J
authors.initials: RJ
authors.lastname: Pearce
authors.forename: K
authors.initials: K
authors.lastname: Russell
authors.forename: J S
authors.initials: JS
authors.lastname: Shaw
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D000700:Analgesics / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D008297:Male; D051379:Mice; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011957:Receptors, Opioid / Q000187:drug effects; D017473:Receptors, Opioid, kappa; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects / Q000378:metabolism
chemical_list: D000081:Acetamides; D000700:Analgesics; D011759:Pyrrolidines; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa