(âË?â??)-cis-N-Normetazocine represents a rigid scaffold able to mimic the tyramine moiety of\nendogenous opioid peptides, and the introduction of different N-substituents influences affinity and\nefficacy of respective ligands at MOR (mu opioid receptor), DOR (delta opioid receptor), and KOR\n(kappa opioid receptor). We have previously identified LP1, a MOR/DOR multitarget opioid ligand,\nwith an N-phenylpropanamido substituent linked to (âË?â??)-cis-N-Normetazocine scaffold. Herein, we\nreport the synthesis, competition binding and calcium mobilization assays of new compounds 10ââ?¬â??16\nthat differ from LP1 by the nature of the N-substituent. In radioligand binding experiments, the\ncompounds 10ââ?¬â??13, featured by an electron-withdrawing or electron-donating group in the para\nposition of phenyl ring, displayed improved affinity for KOR (Ki = 0.85ââ?¬â??4.80 Ã?¼M) in comparison to\nLP1 (7.5 Ã?¼M). On the contrary, their MOR and DOR affinities were worse (Ki = 0.18ââ?¬â??0.28 Ã?¼M and\nKi = 0.38ââ?¬â??1.10 Ã?¼M, respectively) with respect to LP1 values (Ki = 0.049 and 0.033 Ã?¼M). Analogous\ntrends was recorded for the compounds 14ââ?¬â??16, featured by indoline, tetrahydroquinoline, and\ndiphenylamine functionalities in the N-substituent. In calcium mobilization assays, the compound 10\nwith a p-fluorophenyl in the N-substituent shared the functional profile of LP1 (pEC50\nMOR = 7.01),\nalthough it was less active. Moreover, the p-methyl- (11) and p-cyano- (12) substituted compounds\nresulted in MOR partial agonists and DOR/KOR antagonists. By contrast, the derivatives 13ââ?¬â??15\nresulted as MOR antagonists, and the derivative 16 as a MOR/KOR antagonist (pKB\nMOR = 6.12\nand pKB\nKOR = 6.11). Collectively, these data corroborated the critical role of the N-substituent in\n(âË?â??)-cis-N-Normetazocine scaffold. Thus, the new synthesized compounds could represent a template\nto achieve a specific agonist, antagonist, or mixed agonist/antagonist functional profile.
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