Open AccessNovel N-Substituted Benzomorphan-Based Compounds: From MOR-Agonist/DOR-Antagonist to Biased/Unbiased MOR Agonists
Author(s) -
Lorella Pasquinucci,
Carmela Parenti,
M. Carmen RuizCantero,
Zafiroula Georgoussi,
Paschalina Pallaki,
Enrique J. Cobos,
Emanuele Amata,
Agostino Marrazzo,
Orazio Prezzavento,
Elena Arena,
Maria Dichiara,
Loredana Salerno,
Rita Turnaturi
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00549
Subject(s) - agonist , chemistry , antagonist , pharmacology , hyperalgesia , (+) naloxone , potency , opioid , stimulation , partial agonist , stereochemistry , receptor , endocrinology , biochemistry , biology , nociception , in vitro
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.