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

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

  • J Med Chem. 2022 Mar 24;65(6):5095-5112. doi: 10.1021/acs.jmedchem.2c00087.
Piyusha P Pagare 1,  Mengchu Li 1,  Yi Zheng 1,  Abhishek S Kulkarni 1,  Samuel Obeng 1,  Boshi Huang 1,  Christian Ruiz 1,  James C Gillespie 2,  Rolando E Mendez 2,  David L Stevens 2,  Justin L Poklis 2,  Matthew S Halquist 3,  William L Dewey 2,  Dana E Selley 2,  Yan Zhang 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Virginia Commonwealth University, 800 E. Leigh Street, Richmond, Virginia 23219, United States.
  • 2 Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, Richmond, Virginia 23298, United States.
  • 3 Department of Pharmaceutics, Virginia Commonwealth University, 410 North 12th Street, Richmond, Virginia 23298, United States.
PMID: 35255685 DOI: 10.1021/acs.jmedchem.2c00087
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.

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