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Open AccessArticle

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

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Department of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
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Department of Drug Sciences, Pharmacology and Toxicology Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
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Laboratory of Cellular Signaling and Molecular Pharmacology, Institute of Biosciences and Applications, National Centre for Scientific Research “Demokritos” Agia Paraskevi-Attikis, 15310 Athens, Greece
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Department of Medical Sciences, Section of Pharmacology, University of Ferrara, via Fossato di Mortara 19, 44121 Ferrara, Italy
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Department of Drug Sciences, Pharmaceutical Technology Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
*
Author to whom correspondence should be addressed.
Pharmaceuticals 2018, 11(2), 40; https://doi.org/10.3390/ph11020040
Received: 16 April 2018 / Revised: 2 May 2018 / Accepted: 3 May 2018 / Published: 5 May 2018
(−)-cis-N-Normetazocine represents a rigid scaffold able to mimic the tyramine moiety of endogenous opioid peptides, and the introduction of different N-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 N-phenylpropanamido substituent linked to (−)-cis-N-Normetazocine scaffold. Herein, we report the synthesis, competition binding and calcium mobilization assays of new compounds 1016 that differ from LP1 by the nature of the N-substituent. In radioligand binding experiments, the compounds 1013, featured by an electron-withdrawing or electron-donating group in the para position of phenyl ring, displayed improved affinity for KOR (Ki = 0.85–4.80 μM) in comparison to LP1 (7.5 μM). On the contrary, their MOR and DOR affinities were worse (Ki = 0.18–0.28 μM and Ki = 0.38–1.10 μM, respectively) with respect to LP1 values (Ki = 0.049 and 0.033 μM). Analogous trends was recorded for the compounds 1416, featured by indoline, tetrahydroquinoline, and diphenylamine functionalities in the N-substituent. In calcium mobilization assays, the compound 10 with a p-fluorophenyl in the N-substituent shared the functional profile of LP1 (pEC50MOR = 7.01), although it was less active. Moreover, the p-methyl- (11) and p-cyano- (12) substituted compounds resulted in MOR partial agonists and DOR/KOR antagonists. By contrast, the derivatives 1315 resulted as MOR antagonists, and the derivative 16 as a MOR/KOR antagonist (pKBMOR = 6.12 and pKBKOR = 6.11). Collectively, these data corroborated the critical role of the N-substituent in (−)-cis-N-Normetazocine scaffold. Thus, the new synthesized compounds could represent a template to achieve a specific agonist, antagonist, or mixed agonist/antagonist functional profile. View Full-Text
Keywords: opioid receptors; radioligand binding; calcium mobilization; benzomorphan opioid receptors; radioligand binding; calcium mobilization; benzomorphan
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MDPI and ACS Style

Pasquinucci, L.; Parenti, C.; Amata, E.; Georgoussi, Z.; Pallaki, P.; Camarda, V.; Calò, G.; Arena, E.; Montenegro, L.; Turnaturi, R. Synthesis and Structure-Activity Relationships of (−)-cis-N-Normetazocine-Based LP1 Derivatives. Pharmaceuticals 2018, 11, 40.

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