In vitro and in vivo biological activities of SR140333, a novel potent non-peptide tachykinin NK1 receptor antagonist

Eur J Pharmacol. 1993 Dec 21;250(3):403-13. doi: 10.1016/0014-2999(93)90027-f.


(S)1-(2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)pip eridin-3- yl]ethyl)-4-phenyl-1-azoniabicyclo[2.2.2]octane chloride (SR140333) is a new non-peptide antagonist of tachykinin NK1 receptors. SR140333 potently, selectively and competitively inhibited substance P binding to NK1 receptors from various animal species, including humans. In vitro, it was a potent antagonist in functional assays for NK1 receptors such as [Sar9,Met(O2)11]substance P-induced endothelium-dependent relaxation of rabbit pulmonary artery and contraction of guinea-pig ileum. Up to 1 microM, it had no effect in bioassays for NK2 ([beta Ala8]neurokinin A-induced contraction of endothelium-deprived rabbit pulmonary artery) and NK3 ([MePhe7]neurokinin B-induced contraction of rat portal vein) receptors. The antagonism exerted by SR140333 toward NK1 receptors was apparently non-competitive, with pD2' values (antagonism potency evaluated by the negative logarithm of the molar concentration of antagonist that produces a 50% reduction of the maximal response to the agonist) between 9.65 and 10.16 in the different assays. SR140333 also blocked in vitro [Sar9,Met(O2)11]substance P-induced release of acetylcholine from rat striatum. In vivo, SR140333 exerted highly potent antagonism toward [Sar9,Met(O2)11]substance P-induced hypotension in dogs (ED50 = 3 micrograms/kg i.v.), bronchoconstriction in guinea-pig (ED50 = 42 micrograms/kg i.v.) and plasma extravasation in rats (ED50 = 7 micrograms/kg i.v.). Finally, it also blocked the activation of rat thalamic neurons after nociceptive stimulation (ED50 = 0.2 micrograms/kg i.v.).

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Bronchoconstriction / drug effects
  • Capillary Permeability / drug effects
  • Cell Line
  • Dogs
  • Endothelium, Vascular / physiology
  • Guinea Pigs
  • Humans
  • Hypotension / chemically induced
  • Hypotension / drug therapy
  • Male
  • Muscle Relaxation / drug effects
  • Muscle, Smooth / drug effects
  • Neurokinin-1 Receptor Antagonists*
  • Neurons / drug effects
  • Piperidines / pharmacology*
  • Quinuclidines / pharmacology*
  • Rabbits
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Neurokinin-1 / metabolism
  • Substance P / analogs & derivatives
  • Substance P / metabolism
  • Substance P / pharmacology
  • Tumor Cells, Cultured


  • Neurokinin-1 Receptor Antagonists
  • Piperidines
  • Quinuclidines
  • Receptors, Neurokinin-1
  • substance P, Sar(9)-Met(O2)(11)-
  • SR 140333
  • Substance P