Design, Synthesis, and In Vitro Characterization of Proteolytically-Stable Opioid-Neurotensin Hybrid Peptidomimetics.

Autor:	De Neve J; Research Group of Organic Chemistry, Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, 1050 Brussels, Belgium., Breault É; Institut de Pharmacologie de Sherbrooke, Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001, 12e Avenue Nord, J1H 5N4 Sherbrooke, Quebec, Canada., Previti S; Research Group of Organic Chemistry, Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, 1050 Brussels, Belgium., Vangeloven E; Research Group of Organic Chemistry, Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, 1050 Brussels, Belgium., Loranger B; Institut de Pharmacologie de Sherbrooke, Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001, 12e Avenue Nord, J1H 5N4 Sherbrooke, Quebec, Canada., Chartier M; Institut de Pharmacologie de Sherbrooke, Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001, 12e Avenue Nord, J1H 5N4 Sherbrooke, Quebec, Canada., Brouillette R; Institut de Pharmacologie de Sherbrooke, Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001, 12e Avenue Nord, J1H 5N4 Sherbrooke, Quebec, Canada., Lanoie A; Institut de Pharmacologie de Sherbrooke, Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001, 12e Avenue Nord, J1H 5N4 Sherbrooke, Quebec, Canada., Holleran BJ; Institut de Pharmacologie de Sherbrooke, Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001, 12e Avenue Nord, J1H 5N4 Sherbrooke, Quebec, Canada., Longpré JM; Institut de Pharmacologie de Sherbrooke, Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001, 12e Avenue Nord, J1H 5N4 Sherbrooke, Quebec, Canada., Gendron L; Institut de Pharmacologie de Sherbrooke, Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001, 12e Avenue Nord, J1H 5N4 Sherbrooke, Quebec, Canada., Tourwé D; Research Group of Organic Chemistry, Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, 1050 Brussels, Belgium., Sarret P; Institut de Pharmacologie de Sherbrooke, Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001, 12e Avenue Nord, J1H 5N4 Sherbrooke, Quebec, Canada., Ballet S; Research Group of Organic Chemistry, Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, 1050 Brussels, Belgium.
Jazyk:	angličtina
Zdroj:	ACS pharmacology & translational science [ACS Pharmacol Transl Sci] 2024 Aug 19; Vol. 7 (9), pp. 2784-2798. Date of Electronic Publication: 2024 Aug 19 (Print Publication: 2024).
DOI:	10.1021/acsptsci.4c00236
Abstrakt:	Linking an opioid to a nonopioid pharmacophore represents a promising approach for reducing opioid-induced side effects during pain management. Herein, we describe the optimization of the previously reported opioid-neurotensin hybrids (OPNT-hybrids), SBL-OPNT-05 & -10 , containing the μ-/δ-opioid agonist H-Dmt-d-Arg-Aba-β-Ala-NH 2 and NT(8-13) analogs optimized for NTS2 affinity. In the present work, the constrained dipeptide Aba-β-Ala was modified to investigate the optimal linker length between the two pharmacophores, as well as the effect of expanding the aromatic moiety within constrained dipeptide analogs, via the inclusion of a naphthyl moiety. Additionally, the N -terminal Arg residue of the NT(8-13) pharmacophore was substituted with β 3 h Arg. For all analogs, affinity was determined at the MOP, DOP, NTS1, and NTS2 receptors. Several of the hybrid ligands showed a subnanomolar affinity for MOP, improved binding for DOP compared to SBL-OPNT-05 & -10 , as well as an excellent NTS2-affinity with high selectivity over NTS1. Subsequently, the G αi1 and β-arrestin-2 pathways were evaluated for all hybrids, along with their stability in rat plasma. Upon MOP activation, SBL-OPNT-13 and -18 were the least effective at recruiting β-arrestin-2 ( E max = 17 and 12%, respectively), while both compounds were also found to be partial agonists at the G αi1 pathway, despite improved potency compared to DAMGO. Importantly, these analogs also showed a half-life in rat plasma in excess of 48 h, making them valuable tools for future in vivo investigations. Competing Interests: The authors declare no competing financial interest. (© 2024 American Chemical Society.)
Databáze:	MEDLINE
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