Synthesis, opioid receptor binding profile, and antinociceptive activity of 1-azaspiro[4.5]decan-10-yl amides.
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.
Fujimoto
R A
RA
Research Department, Ciba-Geigy Corporation, Summit, New Jersey 07901.
Boxer
J
J
Jackson
R H
RH
Simke
J P
JP
Neale
R F
RF
Snowhill
E W
EW
Barbaz
B J
BJ
Williams
M
M
Sills
M A
MA
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
D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013141:Spiro Compounds