Biochemical and pharmacological activities of SR 144190, a new potent non-peptide tachykinin NK2 receptor antagonist.
(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.).
Emonds-Alt
X
X
Sanofi Recherche, Montpellier, France.
Advenier
C
C
Cognon
C
C
Croci
T
T
Daoui
S
S
Ducoux
J P
JP
Landi
M
M
Naline
E
E
Neliat
G
G
Poncelet
M
M
Proietto
V
V
Van Broeck
D
D
Vilain
P
P
Soubrié
P
P
Le Fur
G
G
Maffrand
J P
JP
Brelière
J C
JC
D000818:Animals; D001667:Binding, Competitive; D001682:Biological Availability; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D004064:Digestive System / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005849:Gerbillinae; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008782:Methylurea Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D009025:Morpholines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*; D012137:Respiratory System / Q000187:drug effects / Q000378:metabolism; D014551:Urinary Tract / Q000187:drug effects / Q000378:metabolism
D008782:Methylurea Compounds; D009025:Morpholines; D018041:Receptors, Neurokinin-2; C110304:SR 144190