8-Carboxamidocyclazocine analogues: redefining the structure-activity relationships of 2,6-methano-3-benzazocines.
Unexpectedly high affinity for opioid receptors has been observed for a novel series of cyclazocine analogues where the prototypic 8-OH was replaced by a carboxamido group. For mu and kappa opioid receptors, the primary carboxamido derivative of cyclazocine ((+/-)-15) displayed high affinity (Ki=0.41 and 0.53 nM, respectively) nearly comparable to cyclazocine. A high enantiopreference ((2R,6R,11R)-) for binding was also observed. Compound (+/-)-15 also displayed potent antinociception activity in mice when administered icv.
Department of Chemistry, Rensselaer Polytechnic Institute, Troy, NY 12180, USA. wentmp@rpi.edu
M P
MP
Wentland
R
R
Lou
Y
Y
Ye
D J
DJ
Cohen
G P
GP
Richardson
J M
JM
Bidlack
D000577:Amides / Q000737:chemistry* / Q000378:metabolism; D018712:Analgesics, Non-Narcotic / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D003496:Cyclazocine / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D009292:Narcotic Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000577:Amides; D018712:Analgesics, Non-Narcotic; D009292:Narcotic Antagonists; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D003496:Cyclazocine