Identification of N-{[6-chloro-4-(2,6-dimethoxyphenyl)quinazolin-2-yl]carbonyl}-l-leucine (NTRC-808), a novel nonpeptide chemotype selective for the neurotensin receptor type 2

Bioorg Med Chem Lett. 2015 Jan 15;25(2):292-6. doi: 10.1016/j.bmcl.2014.11.047. Epub 2014 Nov 24.

Abstract

Compounds acting via the GPCR neurotensin receptor type 2 (NTS2) display analgesic effects in relevant animal models. Using a pharmacophore model based on known NT receptor nonpeptide compounds, we screened commercial databases to identify compounds that might possess activity at NTS2 receptor sites. Modification of our screening hit to include structural features known to be recognized by NTS1 and NTS2, led to the identification of the novel NTS2 selective nonpeptide, N-{[6-chloro-4-(2,6-dimethoxyphenyl)quinazolin-2-yl]carbonyl}-l-leucine (9). This compound is a potent partial agonist in the FLIPR assay with a profile of activity similar to that of the reference NTS2 analgesic nonpeptide levocabastine (5).

Keywords: FLIPR assay; Levocabastine; NTS2 receptor; Neurotensin; Pain; SR142948a; SR48692.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Calcium / metabolism
  • Drug Partial Agonism*
  • Humans
  • Leucine / analogs & derivatives*
  • Leucine / chemistry
  • Leucine / pharmacology
  • Models, Molecular
  • Molecular Structure
  • Quinazolines / chemistry
  • Quinazolines / pharmacology*
  • Radioligand Assay
  • Receptors, Neurotensin / agonists*
  • Structure-Activity Relationship

Substances

  • NTRC-808
  • NTSR2 protein, human
  • Quinazolines
  • Receptors, Neurotensin
  • Leucine
  • Calcium