2. Academic Validation
  3. Discovery of 6α-Thiazolylcarboxamidonaltrexamine Derivative (NTZ) as a Potent and Central Nervous System Penetrant Opioid Receptor Modulator with Drug-like Properties for Potential Treatment of Opioid Use Disorder

Discovery of 6α-Thiazolylcarboxamidonaltrexamine Derivative (NTZ) as a Potent and Central Nervous System Penetrant Opioid Receptor Modulator with Drug-like Properties for Potential Treatment of Opioid Use Disorder

  • ACS Pharmacol Transl Sci. 2024 Dec 5;7(12):4165-4182. doi: 10.1021/acsptsci.4c00593.
Boshi Huang 1,  Hongguang Ma 1,  Piyusha P Pagare 1,  Mengchu Li 1,  Rolando E Mendez 2,  James C Gillespie 2,  Justin L Poklis 2,  Matthew S Halquist 3,  David L Stevens 2,  William L Dewey 2,  Dana E Selley 2,  Yan Zhang 1 2 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, 800 E Leigh Street, Richmond, Virginia23298, United States.
  • 2 Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, 410 North 12th Street, Richmond, Virginia23298, United States.
  • 3 Department of Pharmaceutics, Virginia Commonwealth University, 410 North 12th Street, Richmond, Virginia23298, United States.
  • 4 Institute for Drug and Alcohol Studies, 203 East Cary Street, Richmond, Virginia23298-0059, United States.
PMID: 39698260 DOI: 10.1021/acsptsci.4c00593
Abstract

The development of highly potent and selective μ Opioid Receptor (MOR) modulators with favorable drug-like properties has always been a focus in the opioid domain. Our previous efforts led to the discovery of a lead compound designated as NAT, a potent centrally acting MOR modulator. However, the fact that NAT precipitated considerable withdrawal effects at higher doses largely impaired its further development. In the light of the concept of activity cliff and CNS multiparameter optimization algorithm, a nitrogen atom was incorporated into the thiophene ring of NAT, aiming to preserve desirable pharmacological activities and CNS permeability while alleviating withdrawal symptoms. Among all 16 new analogs, compound 6 (NTZ) exhibited improved Opioid Receptor selectivity, enhanced in vivo antagonistic effect, and overall fewer withdrawal symptoms compared to NAT. Further assessment of several key drug-like properties suggested a favorable ADMET profile of NTZ. Taken together, NTZ shows promise as a potential lead to treat opioid use disorder.

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