Novel N-Substituted Benzomorphan-Based Compounds: From MOR-Agonist/DOR-Antagonist to Biased/Unbiased MOR Agonists.

Abstract

Modifications at the basic nitrogen of the benzomorphan scaffold allowed the development of compounds able to segregate physiological responses downstream of the receptor signaling, opening new possibilities in opioid drug development. Alkylation of the phenyl ring in the N-substituent of the MOR-agonist/DOR-antagonist LP1 resulted in retention of MOR affinity. Moreover, derivatives 7a, 7c, and 7d were biased MOR agonists toward ERK1,2 activity stimulation, whereas derivative 7e was a low potency MOR agonist on adenylate cyclase inhibition. They were further screened in the mouse tail flick test and PGE2-induced hyperalgesia and drug-induced gastrointestinal transit.

• Authors: Lorella Pasquinucci, Carmela Parenti, M Carmen Ruiz-Cantero, Zafiroula Georgoussi, Paschalina Pallaki, Enrique J Cobos, Emanuele Amata, Agostino Marrazzo, Orazio Prezzavento, Emanuela Arena, Maria Dichiara, Loredana Salerno, Rita Turnaturi
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 11 Issue 5 Pg. 678-685 (May 14 2020) ISSN: 1948-5875 [Print] United States
• PMID: 32435370 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 American Chemical Society.