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Papers of the Week

2020 May 14

ACS Med Chem Lett



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


Pasquinucci L, Parenti C, Ruiz-Cantero CM, Georgoussi Z, Pallaki P, Cobos EJ, Amata E, Marrazzo A, Prezzavento O, Arena E, Dichiara M, Salerno L, Turnaturi R
ACS Med Chem Lett. 2020 May 14; 11(5):678-685.
PMID: 32435370.


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 -substituent of the MOR-agonist/DOR-antagonist LP1 resulted in retention of MOR affinity. Moreover, derivatives , , and were biased MOR agonists toward ERK1,2 activity stimulation, whereas derivative 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.