Synthesis and Structure-Activity Relationships of (−)-cis-N-Normetazocine-Based LP1 Derivatives
| Autor: | Rita Turnaturi, Girolamo Calo, Lucia Montenegro, Emanuela Arena, Emanuele Amata, Carmela Parenti, Lorella Pasquinucci, Valeria Camarda, Zafiroula Georgoussi, Paschalina Pallaki |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Agonist medicine.drug_class Stereochemistry Socio-culturale Pharmaceutical Science Benzomorphan Calcium mobilization κ-opioid receptor Partial agonist δ-opioid receptor 03 medical and health sciences chemistry.chemical_compound Radioligand binding Drug Discovery medicine Opioid peptide Opioid receptors Molecular Medicine 3003 Chemistry Antagonist opioid receptors radioligand binding calcium mobilization benzomorphan 030104 developmental biology μ-opioid receptor |
| Zdroj: | Pharmaceuticals; Volume 11; Issue 2; Pages: 40 |
| ISSN: | 1424-8247 |
| DOI: | 10.3390/ph11020040 |
| Popis: | (−)-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 10–16 that differ from LP1 by the nature of the N-substituent. In radioligand binding experiments, the compounds 10–13, 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 14–16, 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 13–15 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. |
| Databáze: | OpenAIRE |
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