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. Epub 2016 Jul 13.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / chemical synthesis
  • Analgesics / chemistry
  • Analgesics / pharmacology
  • Analgesics / therapeutic use*
  • Analysis of Variance
  • Animals
  • Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Bridged Bicyclo Compounds, Heterocyclic / therapeutic use
  • Calcium / metabolism
  • Carboxylic Acids / chemistry*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Hindlimb Suspension
  • Humans
  • Injections, Spinal
  • Male
  • Neurotransmitter Agents / chemical synthesis
  • Neurotransmitter Agents / chemistry
  • Neurotransmitter Agents / pharmacology*
  • Pain / drug therapy*
  • Pain / physiopathology
  • Piperidines / chemistry*
  • Protein Binding / drug effects
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Reaction Time / drug effects
  • Receptors, Neurotensin / antagonists & inhibitors*
  • Receptors, Neurotensin / metabolism*

Substances

  • Analgesics
  • Bridged Bicyclo Compounds, Heterocyclic
  • Carboxylic Acids
  • NTRC-844
  • Neurotransmitter Agents
  • Piperidines
  • Pyrazoles
  • Receptors, Neurotensin
  • Calcium

Grant support