Asymmetric synthesis and receptor activity of chiral simplified resiniferatoxin (sRTX) analogues as transient receptor potential vanilloid 1 (TRPV1) ligands

  • Bioorg Med Chem Lett. 2014 Jan 1;24(1):382-5. doi: 10.1016/j.bmcl.2013.10.064.
Myeong Seop Kim  1 ,  Yooran Ki  1 ,  Song Yeon Ahn  1 ,  Suyoung Yoon  1 ,  Sung-Eun Kim  1 ,  Hyeung-Geun Park  1 ,  Wei Sun  2 ,  Karam Son  3 ,  Minghua Cui  3 ,  Sun Choi  3 ,  Larry V Pearce  4 ,  Timothy E Esch  4 ,  Ian A Deandrea-Lazarus  4 ,  Peter M Blumberg  4 ,  Jeewoo Lee  5
Affiliations
  • 1. Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
  • 2. Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China.
  • 3. National Leading Research Lab of Molecular Modeling & Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences and Global Top 5 Research Program, Ewha Womans University, Seoul 120-750, Republic of Korea.
  • 4. Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
  • 5. Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address: [email protected].
PMID: 24321344 DOI: 10.1016/j.bmcl.2013.10.064
Abstract

The chiral isomers of the two potent simplified RTX-based vanilloids, compounds 2 and 3, were synthesized employing highly enantioselective PTC alkylation and evaluated as hTRPV1 ligands. The analysis indicated that the R-isomer was the eutomer in binding affinity and functional activity. The agonism of compound 2R was comparable to that of RTX. Docking analysis of the chiral isomers of 3 suggested the basis for its stereospecific activity and the binding mode of 3R.

Keywords
Capsaicin; Molecular modeling; Resiniferatoxin; TRPV1 antagonist; Vanilloid receptor 1.