Synthesis and Structure-Activity Relationships of (−)-cis-N-Normetazocine-Based LP1 Derivatives.

(−)-<italic>cis</italic>-<italic>N</italic>-Normetazocine represents a rigid scaffold able to mimic the tyramine moiety of endogenous opioid peptides, and the introduction of different <italic>N</italic>-substituents influences affinity and efficacy of respective ligands at MOR (mu opioid receptor), DOR (delta opioid receptor), and KOR (kappa opioid receptor). We have previously identified LP1, a MOR/DOR multitarget opioid ligand, with an <italic>N</italic>-phenylpropanamido substituent linked to (−)-<italic>cis</italic>-<italic>N</italic>-Normetazocine scaffold. Herein, we report the synthesis, competition binding and calcium mobilization assays of new compounds <bold>10</bold>–<bold>16</bold> that differ from LP1 by the nature of the <italic>N</italic>-substituent. In radioligand binding experiments, the compounds <bold>10</bold>–<bold>13</bold>, featured by an electron-withdrawing or electron-donating group in the para position of phenyl ring, displayed improved affinity for KOR (K_i = 0.85–4.80 μM) in comparison to LP1 (7.5 μM). On the contrary, their MOR and DOR affinities were worse (K_i = 0.18–0.28 μM and K_i = 0.38–1.10 μM, respectively) with respect to LP1 values (K_i = 0.049 and 0.033 μM). Analogous trends was recorded for the compounds <bold>14</bold>–<bold>16</bold>, featured by indoline, tetrahydroquinoline, and diphenylamine functionalities in the <italic>N</italic>-substituent. In calcium mobilization assays, the compound <bold>10</bold> with a <italic>p</italic>-fluorophenyl in the <italic>N</italic>-substituent shared the functional profile of LP1 (pEC₅₀^MOR = 7.01), although it was less active. Moreover, the <italic>p</italic>-methyl- (<bold>11</bold>) and <italic>p</italic>-cyano- (<bold>12</bold>) substituted compounds resulted in MOR partial agonists and DOR/KOR antagonists. By contrast, the derivatives <bold>13</bold>–<bold>15</bold> resulted as MOR antagonists, and the derivative <bold>16</bold> as a MOR/KOR antagonist (pK_B^MOR = 6.12 and pK_B^KOR = 6.11). Collectively, these data corroborated the critical role of the <italic>N</italic>-substituent in (−)-<italic>cis</italic>-<italic>N</italic>-Normetazocine scaffold. Thus, the new synthesized compounds could represent a template to achieve a specific agonist, antagonist, or mixed agonist/antagonist functional profile. [ABSTRACT FROM AUTHOR]