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Open AccessArticle

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

Department of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
Department of Drug Sciences, Pharmacology and Toxicology Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
Laboratory of Cellular Signaling and Molecular Pharmacology, Institute of Biosciences and Applications, National Centre for Scientific Research “Demokritos” Agia Paraskevi-Attikis, 15310 Athens, Greece
Department of Medical Sciences, Section of Pharmacology, University of Ferrara, via Fossato di Mortara 19, 44121 Ferrara, Italy
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;
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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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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