In vitro and in vivo biological activities of SR140333, a novel potent non-peptide tachykinin NK1 receptor antagonist.
(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.).
Emonds-Alt
X
X
Sanofi Recherche, Montpellier, France.
Doutremepuich
J D
JD
Heaulme
M
M
Neliat
G
G
Santucci
V
V
Steinberg
R
R
Vilain
P
P
Bichon
D
D
Ducoux
J P
JP
Proietto
V
V
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016084:Bronchoconstriction / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D002460:Cell Line; D004285:Dogs; D004730:Endothelium, Vascular / Q000502:physiology; D006168:Guinea Pigs; D006801:Humans; D007022:Hypotension / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D064729:Neurokinin-1 Receptor Antagonists; D009474:Neurons / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D011812:Quinuclidines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013373:Substance P / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D011812:Quinuclidines; D018040:Receptors, Neurokinin-1; C062618:substance P, Sar(9)-Met(O2)(11)-; C085215:SR 140333; D013373:Substance P