GR159897, a potent non-peptide antagonist at tachykinin NK2 receptors.
GR159897 ((R)-1-[2-(5-fluoro-1H-indol-3-yl)ethyl]-4-methoxy-4- [(phenylsulfinyl)methyl]piperidine) is a novel, highly potent and selective non-peptide antagonist at tachykinin NK2 receptors. GR159897 inhibited binding of the NK2 receptor antagonist radioligand [3H]cyclohexylcarbonyl-Gly-Ala-(D)Trp-Phe-NMe2 ([3H]GR100679) to human ileum NK2 receptors transfected into Chinese hamster ovary cells (pKi 9.5) and to rat colon membranes (pKi 10.0). GR159897 was a competitive antagonist of contractions induced by the NK2 receptor agonist [Lys3,Gly8-R-gamma-lactam-Leu9]neurokinin A-(3-10) (GR64349) in guinea-pig trachea (pA2 8.7), and had negligible activity at human NK1 receptors transfected into Chinese hamster ovary cells (pKi 5.3), NK1 receptors in guinea-pig trachea (pKB < 5) or NK3 receptors in guinea-pig cerebral cortex (pKi < 5). In vivo, in the anaesthetised guinea-pig, GR159897 (0.12 mg.kg-1 i.v.) potently antagonised bronchoconstriction induced by GR64349 (dose-ratio = 28), with a long duration of action (3 h). GR159897 should be a useful tool for studying the physiological and pathophysiological role of tachykinin NK2 receptor activation.
Beresford
I J
IJ
Department of Pharmacology, Glaxo Research and Development Ltd, Ware, Herts., UK.
Sheldrick
R L
RL
Ball
D I
DI
Turpin
M P
MP
Walsh
D M
DM
Hawcock
A B
AB
Coleman
R A
RA
Hagan
R M
RM
Tyers
M B
MB
D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D009842:Oligopeptides / Q000378:metabolism; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*; D014132:Trachea / Q000187:drug effects / Q000502:physiology
C092990:GR 159897; D007211:Indoles; D009842:Oligopeptides; D010880:Piperidines; D018041:Receptors, Neurokinin-2; C083380:GR 100679