Molecular Pharmacology Profiling of Phenylfentanil and Its Analogues to Understand the Putative Involvement of an Adrenergic Mechanism in Fentanyl-Induced Respiratory Depression

While there are approved therapeutics to treat opioid
overdoses,
the need for treatments to reverse overdoses due to ultrapotent fentanyls
remains unmet. This may be due in part to an adrenergic mechanism
of fentanyls in addition to their stereotypical mu-opioid receptor
(MOR) effects. Herein, we report our efforts to further understanding
of the functions these distinct mechanisms impart. Employing the known
MOR neutral antagonist phenylfentanil as a lead, 17 analogues were
designed based on the concept of isosteric replacement. To probe mechanisms
of action, these analogues were pharmacologically evaluated in vitro
and in vivo, while in silico modeling studies were also conducted
on phenylfentanil. While it did not indicate MOR involvement in vivo,
phenylfentanil yielded respiratory minute volumes similar to those
caused by fentanyl. Taken together with molecular modeling studies,
these results indicated that respiratory effects of fentanyls may
also correlate to inhibition of both α1A- and α1B-adrenergic
receptors.