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.

Figure 1.

Chemical structures of FDA-approved opioid ligands as opioid use disorder treatments.

Figure 2.

Molecular design of NAP derivatives.

Figure 3.

Water–water tail immersion assay results of (A) 6α-analogs (n = 6) as agonists at a single dose of 10 mg/kg s.c., (B) 6β-analogs (n = 6) as agonists at a single dose of 10 mg/kg s.c., and (C) compounds as antagonists at a single dose of 10 mg/kg s.c. in the presence of morphine (10 mg/kg). Saline and morphine were used as the negative and positive controls, respectively. Data are presented as mean values ± SD. *P < 0.05, **P < 0.01, and ***P < 0.0005, ****P < 0.0001, compared to 10 mg/kg morphine (s.c.).

Figure 4.

In vivo withdrawal assays of compounds 25, 26, and 31 in morphine-pelleted mice (n = 6), including (A) wet dog shakes, (B) jumps, and (C) paw tremors. All compounds were administered s.c. *P < 0.05, **P < 0.01, and ***P < 0.0005, ****P < 0.0001, compared to 1 mg/kg naloxone (NLX; s.c.).

Scheme 1.

Synthetic Route for Target Compounds