Abstract:
: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.
journal_name
Bioorg Med Chem Lettjournal_title
Bioorganic & medicinal chemistry lettersauthors
Fujii H,Ida Y,Hanamura S,Osa Y,Nemoto T,Nakajima M,Hasebe K,Nakao K,Mochizuki H,Nagase Hdoi
10.1016/j.bmcl.2010.07.035subject
Has Abstractpub_date
2010-09-01 00:00:00pages
5035-8issue
17eissn
0960-894Xissn
1464-3405pii
S0960-894X(10)00991-1journal_volume
20pub_type
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