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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.

SUBMITTER: Pasquinucci L

PROVIDER: S-EPMC7236032 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

Pasquinucci Lorella L Parenti Carmela C Ruiz-Cantero M Carmen MC Georgoussi Zafiroula Z Pallaki Paschalina P Cobos Enrique J EJ Amata Emanuele E Marrazzo Agostino A Prezzavento Orazio O Arena Emanuela E Dichiara Maria M Salerno Loredana L Turnaturi Rita R

ACS medicinal chemistry letters 20200128 5

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 de ...[more]

PMID: 32435370

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