2. Academic Validation
  3. Synthesis and evaluation of 3,4,5-trisubstituted triazoles as G protein-biased kappa opioid receptor agonists

Synthesis and evaluation of 3,4,5-trisubstituted triazoles as G protein-biased kappa opioid receptor agonists

  • Eur J Med Chem. 2024 Jun 27:276:116627. doi: 10.1016/j.ejmech.2024.116627.
Ashley E Trojniak 1,  Vuong Q Dang 2,  Kerri M Czekner 3,  Robin J Russo 3,  Lilyan M Mather 1,  Edward L Stahl 2,  Michael D Cameron 2,  Laura M Bohn 3,  Jeffrey Aubé 4
Affiliations

Affiliations

  • 1 Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7363, USA.
  • 2 The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, 130 Scripps Way, Jupiter, FL, 33458, USA.
  • 3 The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, 130 Scripps Way, Jupiter, FL, 33458, USA; The Skaggs Graduate School of Chemical and Biological Sciences at Scripps Research, Jupiter, FL, 33458, USA.
  • 4 Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7363, USA. Electronic address: jaube@unc.edu.
PMID: 38971050 DOI: 10.1016/j.ejmech.2024.116627
Abstract

Kappa Opioid Receptor (KOR) agonists represent promising therapeutics for pain relief due to their analgesic properties along with lower abuse potential than opioids that act at the mu Opioid Receptor. However, typical KOR agonists produce sedation and dysphoria. Previous studies have shown that G protein signaling-biased KOR agonists may present a means to untangle the desired analgesic properties from undesired side effects. In this paper, we report a new series of G protein signaling-biased KOR agonists entailing -S- → -CH2- replacement in a previously reported KOR agonist, triazole 1.1. With an optimized carbon linker in hand, further development of the scaffold was undertaken to investigate the appendages of the triazole core. The structure-activity relationship study of this series is described, including several analogues that display enhanced potency while maintaining G protein-signaling bias compared to triazole 1.1.

Keywords

Biased agonist; Bioisostere; Kappa opioid receptor; Microsomal stability; Structure–activity relationships.

Figures
Products