Biochemical and pharmacological activities of SR 144190, a new potent non-peptide tachykinin NK2 receptor antagonist

Neuropeptides. 1997 Oct;31(5):449-58. doi: 10.1016/s0143-4179(97)90039-1.

Abstract

(R)-3-(1-[2-(4-benzoyl-2-(3,4-difluorophenyl)-morpholin-2-yl)- ethyl]-4-phenylpiperidin-4-yl)-1-dimethylurea (SR 144190) is a new non-peptide antagonist of tachykinin NK2 receptors. SR 144190 potently and selectively inhibited neurokinin A binding to NK2 receptors from various species, including humans. In in vitro functional assays, it was a potent, selective and competitive antagonist of NK2 receptors with apparent affinities (pA2 values) between 9.08 and 10.10. In vivo, SR 144190 blocked [Nle10]neurokinin A-(4-10)-induced bronchoconstriction in guinea pigs (ID50 = 21 micrograms kg-1 i.v. and 250 micrograms kg-1 i.d.) and [beta Ala8]neurokinin A-(4-10)-induced urinary bladder contraction in rats (ID50 = 11 micrograms kg-1 i.v. and 190 micrograms kg-1 i.d.). It prevented citric acid-induced cough and airway hyperresponsiveness to acetylcholine in guinea pigs (1 mg kg-1 i.p.) as well as castor oil-induced diarrhoea in rats (0.01-10 micrograms kg-1 s.c. or p.o). Finally, it blocked the turning behaviour induced by intrastriatal injections of [Nle10]neurokinin A-(4-10) in mice (ID50 = 3 micrograms kg-1 i.v. and 16 micrograms kg-1 p.o.).

MeSH terms

  • Animals
  • Binding, Competitive
  • Biological Availability
  • Central Nervous System / drug effects
  • Central Nervous System / metabolism
  • Cricetinae
  • Digestive System / drug effects
  • Digestive System / metabolism
  • Female
  • Gerbillinae
  • Guinea Pigs
  • Humans
  • In Vitro Techniques
  • Male
  • Methylurea Compounds / chemistry
  • Methylurea Compounds / pharmacokinetics
  • Methylurea Compounds / pharmacology*
  • Mice
  • Morpholines / chemistry
  • Morpholines / pharmacokinetics
  • Morpholines / pharmacology*
  • Rats
  • Receptors, Neurokinin-2 / antagonists & inhibitors*
  • Respiratory System / drug effects
  • Respiratory System / metabolism
  • Urinary Tract / drug effects
  • Urinary Tract / metabolism

Substances

  • Methylurea Compounds
  • Morpholines
  • Receptors, Neurokinin-2
  • SR 144190