Effect of a 6-cyano substituent in 14-oxygenated N-methylmorphinans on opioid receptor binding and antinociceptive potency.
In a continued effort to find new substitution patterns in morphinans that would produce strong antinociception while inducing lesser side effects, 4,5-oxygen bridge-opened 6-cyano-substituted N-methylmorphinans (1-3) were synthesized. All compounds showed high affinities in the low nanomolar range to the mu opioid receptor and decreased interaction with delta and kappa receptors, thus being mu selective. When tested in vivo, the 6-cyanomorphinanas acted as potent antinociceptive agents which were either more active or equipotent to their 6-keto analogues 4-6.
Spetea
Mariana
M
Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innrain 52a, A-6020 Innsbruck, Austria. Mariana.Spetea@uibk.ac.at
Greiner
Elisabeth
E
Aceto
Mario D
MD
Harris
Louis S
LS
Coop
Andrew
A
Schmidhammer
Helmut
H
D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism; D066298:In Vitro Techniques; D051379:Mice; D008813:Mice, Inbred ICR; D009019:Morphinans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011957:Receptors, Opioid / Q000187:drug effects* / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000187:drug effects / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000187:drug effects / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
D000700:Analgesics; D009019:Morphinans; D009570:Nitriles; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu