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 towards 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.
Novel N-Substituted Benzomorphan-Based Compounds: From MOR-Agonist/DOR-Antagonist to Biased/Unbiased MOR Agonists
Pasquinucci LorellaPrimo
;Parenti Carmela
;Amata Emanuele;Marrazzo Agostino;Prezzavento Orazio;Arena Emanuela;Dichiara Maria;Salerno Loredana;Turnaturi Rita
Ultimo
2020-01-01
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 towards 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.File | Dimensione | Formato | |
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ACS medicinal chemistry letters versione accettata.pdf
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Novel N-Substituted Benzomorphan-Based Compounds_ From MOR-Agonist_DOR-Antagonist to Biased_Unbiased MOR Agonists.pdf
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