Synthesis and biochemical evaluation of 17-N-beta-aminoalkyl-4,5α-epoxynormorphinans

Ötvös, Ferenc and Szűcs, Edina and Urai, Ákos and Köteles, István and Szabó, Pál Tamás and Varga, Zsuzsanna Katalin and Gombos, Dávid and Hosztafi, Sándor and Benyhe, Sándor (2023) Synthesis and biochemical evaluation of 17-N-beta-aminoalkyl-4,5α-epoxynormorphinans. SCIENTIFIC REPORTS, 13 (1). No-20305. ISSN 2045-2322

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Abstract

Opiate alkaloids and their synthetic derivatives are still widely used in pain management, drug addiction, and abuse. To avoid serious side effects, compounds with properly designed pharmacological profiles at the opioid receptor subtypes are long needed. Here a series of 17- N -substituted derivatives of normorphine and noroxymorphone analogues with five- and six-membered ring substituents have been synthesized for structure–activity study. Some compounds showed nanomolar affinity to MOR, DOR and KOR in in vitro competition binding experiments with selective agonists [ 3 H]DAMGO, [ 3 H]Ile 5,6 -deltorphin II and [ 3 H]HS665, respectively. Pharmacological characterization of the compounds in G-protein signaling was determined by [ 35 S]GTPγS binding assays. The normorphine analogues showed higher affinity to KOR compared to MOR and DOR, while most of the noroxymorphone derivatives did not bind to KOR. The presence of 14-OH substituent resulted in a shift in the pharmacological profiles in the agonist > partial agonist > antagonist direction compared to the parent compounds. A molecular docking-based in silico method was also applied to estimate the pharmacological profile of the compounds. Docking energies and the patterns of the interacting receptor atoms, obtained with experimentally determined active and inactive states of MOR, were used to explain the observed pharmacological features of the compounds.

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