Synthesis of pyrrolomorphinan derivatives as kappa opioid agonists.
We synthesized pyrrolomorphinan derivatives 6, 7, and 9 to examine whether the pyrrole ring would be an accessory site in the kappa opioid receptor selective antagonist, nor-binaltorphimine. Derivative 6 had an alpha,beta-unsaturated ketone substituent that strongly bound to the kappa receptor. The compound with the highest kappa receptor selectivity, 6e, produced a dose-dependent antinociceptive effect in the mouse acetic acid writhing test. However, derivatives 7 and 9, which did not have alpha,beta-unsaturated ketone substituents, showed less kappa receptor selectivity than compound 6. Based on structure-activity relationships, we proposed that these compounds adopted active structures for kappa selective agonist activity. The pyrrole ring would not function as an accessory site, but the ability of the side chain on the pyrrole ring to localize above the C-ring appeared to confer kappa selective agonist activity. These results will promote the design of novel kappa agonists.
Fujii
Hideaki
H
School of Pharmacy, Kitasato University, Tokyo, Japan.
Ida
Yoshihiro
Y
Hanamura
Shinichi
S
Osa
Yumiko
Y
Nemoto
Toru
T
Nakajima
Mayumi
M
Hasebe
Ko
K
Nakao
Kaoru
K
Mochizuki
Hidenori
H
Nagase
Hiroshi
H
D009019:Morphinans / Q000138:chemical synthesis* / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology*; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D013329:Structure-Activity Relationship
D009019:Morphinans; D011758:Pyrroles; D017473:Receptors, Opioid, kappa