Design, Synthesis, and Biological Evaluation of NAP Isosteres: A Switch from Peripheral to Central Nervous System Acting Mu-Opioid Receptor Antagonists

Abstract

The μ opioid receptor (MOR) has been an intrinsic target to develop treatment of opioid use disorders (OUD). Herein, we report our efforts on developing centrally acting MOR antagonists by structural modifications of 17-cyclopropylmethyl-3,14-dihydroxy-4,5α-epoxy-6β-[(4′-pyridyl) carboxamido] morphinan (NAP), a peripherally acting MOR-selective antagonist. An isosteric replacement concept was applied and incorporated with physiochemical property predictions in the molecular design. Three analogs, namely, 25, 26, and 31, were identified as potent MOR antagonists in vivo with significantly fewer withdrawal symptoms than naloxone observed at similar doses. Furthermore, brain and plasma drug distribution studies supported the outcomes of our design strategy on these compounds. Taken together, our isosteric replacement of pyridine with pyrrole, furan, and thiophene provided insights into the structure–activity relationships of NAP and aided the understanding of physicochemical requirements of potential CNS acting opioids. These efforts resulted in potent, centrally efficacious MOR antagonists that may be pursued as leads to treat OUD.

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

“…We first characterized the target fentanyl analogues with the radioligand competition binding assay and the MOR [ 35 S]-GTPγS functional assay following previously described procedures. − The purpose of these two experiments was to determine the binding affinity at the three opioid receptors and to assess their functional potencies and efficacies at the MOR, respectively.…”

Structural Alterations of the “Address” Moiety of NAN Leading to the Discovery of a Novel Opioid Receptor Modulator with Reduced hERG Toxicity

“…All compounds were then tested by warm-water tail immersion assays to evaluate their capacity to produce antinociception or block the antinociception elicited by morphine in mice following previously described protocol . In this assay, a single dose (10 mg/kg) was applied because it has been proven to be a practical and efficient screening approach in our laboratories to sort out the ligands with agonism or antagonism in vivo. ,,, The outcomes were presented as the percentage of maximum possible effect (% MPE). As seen in Figure A,B, compounds 7 , 9 , and 13 (10 mg/kg) showed noticeable antinociception with relatively high % MPE values, which appeared to correspond to their moderate efficacy observed in the [ 35 S]-GTPγS functional assay.…”