Identification of 2-({[1-(4-Fluorophenyl)-5-(2-methoxyphenyl)-1H-pyrazol-3-yl]carbonyl}amino)tricyclo[3.3.1.13,7]decane-2-carboxylic Acid (NTRC-844) as a Selective Antagonist for the Rat Neurotensin Receptor Type 2

  • ACS Chem Neurosci. 2016 Sep 21;7(9):1225-31. doi: 10.1021/acschemneuro.6b00097.
James B Thomas  1 ,  Mélanie Vivancos  2 ,  Angela M Giddings  1 ,  Robert W Wiethe  1 ,  Keith R Warner  1 ,  Alexandre Murza  2 ,  Élie Besserer-Offroy  2 ,  Jean-Michel Longpré  2 ,  Scott P Runyon  1 ,  Ann M Decker  1 ,  Brian P Gilmour  1 ,  Philippe Sarret  2
Affiliations
  • 1. Center for Drug Discovery, RTI International , P.O. Box 12194, Research Triangle Park, North Carolina 27709, United States.
  • 2. Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke , 3001, 12th Ave. North, Sherbrooke, QC J1H 5N4, Canada.
PMID: 27359371 DOI: 10.1021/acschemneuro.6b00097
Abstract

Neurotensin Receptor type 2 (NTS2) compounds display analgesic activity in animal pain models. We have identified the first high-affinity NTS2-selective antagonist (8) that is active in vivo. This study also revealed that the NTS2 FLIPR assay designation for a compound, agonist, partial agonist, and so forth, did not correlate with its in vivo activity as observed in the thermal tail-flick acute model of pain. This suggests that calcium mobilization is not the signaling pathway involved in NTS2-mediated analgesia as assessed by the thermal tail-flick model. Finally, we found a significant bias between rat and human for compound 9 in the NTS2 binding assay.

Keywords
FLIPR assay; NT79; NTRC-844; NTS2 receptor; Neurotensin; analgesia; thermal tail-flick.
Products