Synthesis and Biological Evaluation of Fentanyl Analogues Modified at Phenyl Groups with Alkyls

Abstract

A series of fentanyl analogues modified at the phenyl group of the phenethyl with alkyl and/or hydroxyl and alkoxy, and the phenyl group in the anilido moiety replaced with benzyl or substituted benzyl, were synthesized. The in vitro opioid receptor functional activity of these compounds was evaluated by assessment of their ability to modulate forskolin-stimulated cAMP accumulation and by their ability to induce β-arrestin2 recruitment. Compound 12 is a potent μ-opioid (MOP) receptor agonist, a potent κ-opioid (KOP) receptor antagonist with weak β-arrestin2 recruitment activity. Compounds 10 and 11 are potent MOP receptor agonists with weak δ-opioid (DOP) receptor antagonist activity and moderate KOP receptor antagonist activity as well as weak β-arrestin2 recruitment activity at the MOP receptor. These compounds are promising leads for discovery of potent opioid analgesics with reduced side effects relative to clinically available strong opioid analgesics.

In vitro functional assays as a tool to study new synthetic opioids at the μ-opioid receptor: Potential, pitfalls and progress

“…Following isolation, cAMP accumulation can be quantified via autoradiography. Other cAMP-measuring assays include radioimmunoassays (RIA) (Costa et al, 1992;Bot et al, 1998;Koch et al, 2005), enzyme immunoassays (EIA) (Gharagozlou et al, 2003;Hsu, Mallareddy, et al, 2019;Crowley et al, 2020), (homogeneous) time resolved fluorescence resonance energy transfer (HTRF or TR-FRET) (Nickolls et al, 2011;Schmid et al, 2017;Feasel & Moran, 2018;Hsu, Walz, et al, 2019;Obeng et al, 2020) and AlphaScreen® assays (Cai et al, 2014;Qin et al, 2019), each based on the competition between a cAMP tracer and unlabeled, intracellular cAMP for labeled anti-cAMP antibodies. Luminescence-based assays, such as the cAMP-Glo® assay (Li et al, 2017), have also been used for ligand screening at MOR (Kanamori et al, 2021a(Kanamori et al, , 2021b.…”

Fentanyl Structure as a Scaffold for Opioid/Non-Opioid Multitarget Analgesics

“…The MOR antagonism confirmed for a few analogues seems particularly worth noting since opioid antagonism in fentanyl-based compounds is rather uncommon. In the numerous family of fentanyls, only few such examples are known [ 58 , 59 ]. This is in marked contrast to the alkaloid opioid receptor ligands, among which many compounds with varying functional properties have been described.…”

DARK Classics in Chemical Neuroscience: Carfentanil

“…A number of research groups are currently working toward the development of safer synthetic fentanyl-type molecules and have reported encouraging results. Current approaches include the development of vaccines, G protein-biased derivatives, and novel fluorinated analogues. − Although many of these recent studies focus on fentanyl derivatives in a broad sense, there are also interesting reports on medicinal chemistry specific to carfentanil. Expanding on the carfentanil amide analogues synthesized by the Ugi multicomponent reaction (see Scheme ), Gutridge and colleagues have recently characterized one such analogue, MP102, as a G protein-biased agonist and showed that the compound reduced alcohol intake in C57BL/6 mice .…”