title: 2-(3,4-Dichlorophenyl)-N-methyl-N-[2-(1-pyrrolidinyl)-1-substituted- ethyl]-acetamides: the use of conformational analysis in the development of a novel series of potent opioid kappa agonists.
abstract: This paper describes the synthesis of a series of N-[2-(1-pyrrolidinyl)ethyl]acetamides (1), methylated at C1 and/or C2 of the ethyl linking group, and their biological evaluation as opioid kappa agonists. Conformational analysis of corresponding desaryl analogues 2 suggested that only those compounds capable of occupying an energy minimum close to that of the known kappa agonist N-[2-(1-pyrrolidinyl)cyclohexyl] acetamide U-50488 might possess kappa agonist properties. Starting from chiral amino acids, other alkyl and aryl substituents were introduced at C1 of the ethyl-linking moiety, giving compounds capable of adopting the same conformation as U-50488. The most potent of these, 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl] acetamide (8), was 146-fold more active than U-50488 in vitro in the mouse vas deferens model and exhibited potent naloxone-reversible analgesic effects (ED50 = 0.004 mg/kg sc) in an abdominal constriction model.
authors.affiliation: ICI Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, England.
authors.forename: G F
authors.initials: GF
authors.lastname: Costello
authors.forename: R
authors.initials: R
authors.lastname: James
authors.forename: J S
authors.initials: JS
authors.lastname: Shaw
authors.forename: A M
authors.initials: AM
authors.lastname: Slater
authors.forename: N C
authors.initials: NC
authors.lastname: Stutchbury
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000698:Analgesia; D000700:Analgesics / Q000138:chemical synthesis*; D000818:Animals; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008968:Molecular Conformation; D015394:Molecular Structure; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009270:Naloxone / Q000378:metabolism; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011957:Receptors, Opioid / Q000187:drug effects* / Q000378:metabolism; D017450:Receptors, Opioid, mu; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology; D014961:X-Ray Diffraction
chemical_list: D000081:Acetamides; D000700:Analgesics; D007202:Indicators and Reagents; D011759:Pyrrolidines; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D009270:Naloxone