title: Synthesis, opioid receptor binding profile, and antinociceptive activity of 1-azaspiro[4.5]decan-10-yl amides.
abstract: A series of azaspiro[4.5]decanyl amides were prepared by a novel cyclization route and examined for opiate receptor binding and antinociceptive activity. Selected tertiary amides in this series showed potent selective mu-receptor binding and antinociceptive activity, in contrast to the less conformationally restricted secondary amides, which showed relatively weak activity. Although structurally similar to the kappa-agonist U-50488H (1), these compounds showed virtually no tendency to bind to the kappa-receptor. An X-ray crystal structure of compound (21) confirms that the spirocyclic amine does not cause distortion away from the chair conformation of the cyclohexane ring. Either this receptor has very specific requirements for the orientation of the two nitrogens of these compounds or this ring system fills a portion of space more readily tolerated by the mu- and delta-receptors.
authors.affiliation: Research Department, Ciba-Geigy Corporation, Summit, New Jersey 07901.
authors.forename: R A
authors.initials: RA
authors.lastname: Fujimoto
authors.forename: J
authors.initials: J
authors.lastname: Boxer
authors.forename: R H
authors.initials: RH
authors.lastname: Jackson
authors.forename: J P
authors.initials: JP
authors.lastname: Simke
authors.forename: R F
authors.initials: RF
authors.lastname: Neale
authors.forename: E W
authors.initials: EW
authors.lastname: Snowhill
authors.forename: B J
authors.initials: BJ
authors.lastname: Barbaz
authors.forename: M
authors.initials: M
authors.lastname: Williams
authors.forename: M A
authors.initials: MA
authors.lastname: Sills
mesh_terms: D000698:Analgesia; D000818:Animals; D001921:Brain / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D008968:Molecular Conformation; D015394:Molecular Structure; D010147:Pain Measurement; D011957:Receptors, Opioid / Q000378:metabolism*; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000378:metabolism; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
chemical_list: D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013141:Spiro Compounds