Biochemical and pharmacological activities of SSR 146977, a new potent nonpeptide tachykinin NK3 receptor antagonist.
SSR 146977 is a potent and selective antagonist of the tachykinin NK3 receptor. In Chinese hamster ovary cells expressing the human tachykinin NK3 receptor, SSR 146977 inhibited the binding of radioactive neurokinin B to NK3 receptors (Ki = 0.26 nM), senktide (10 nM) induced inositol monophosphate formation (IC50 = 7.8-13 nM), and intracellular calcium mobilization (IC50 = 10 nM). It antagonized [MePhe7]neurokinin B induced contractions of guinea pig ileum (pA2 = 9.07). Senktide (30 nM) induced firing rate increase of noradrenergic neurons in the guinea pig locus coeruleus and dopaminergic neurons in the guinea pig substantia nigra was also blocked by SSR 146977 (50 and 100 nM, respectively). In vivo, in the respiratory system, SSR 146977 inhibited bronchial hyperresponsiveness to acetylcholine, bronchial microvascular permeability hypersensitivity to histamine (doses of 0.1-1 mg/kg i.p.), and cough (doses of 0.03-1 mg/kg i.p.) provoked by citric acid in guinea pigs. In the central nervous system, SSR 146977 inhibited turning behaviour (ID50 = 0.2 mg/kg i.p. and 0.4 mg/kg p.o.) and prevented the decrease of locomotor activity (10 and 30 mg/kg i.p) mediated by the stimulation of NK3 receptors in gerbils. In guinea pigs, SSR 146977 antagonized senktide-induced acetylcholine release in the hippocampus (0.3 and 1 mg/kg i.p) and norepinephrine release in the prefrontal cortex (0.3 mg/kg i.p.). It also prevented haloperidol-induced increase of the number of spontaneously active dopamine A10 neurons (1 and 3 mg/kg i.p.).
Emonds-Alt
Xavier
X
Sanofi-Synthelabo Recherche, Montpellier, France. xavier.emonds-alt@sanofi-synthelabo.com
Proietto
Vincenzo
V
Steinberg
Régis
R
Advenier
Charles
C
Daoui
Samira
S
Naline
Emmanuel
E
Gueudet
Christiane
C
Michaud
Jean-Claude
JC
Oury-Donat
Florence
F
Poncelet
Martine
M
Vilain
Pol
P
Le Fur
Gérard
G
Maffrand
Jean-Pierre
JP
Soubrié
Philippe
P
Pascal
Marc
M
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D005849:Gerbillinae; D006168:Guinea Pigs; D006801:Humans; D008782:Methylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D015287:Neurokinin B / Q000378:metabolism / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013373:Substance P / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
D008782:Methylurea Compounds; D010446:Peptide Fragments; D010880:Piperidines; D018042:Receptors, Neurokinin-3; C468909:SSR 146977; C054724:senktide; D013373:Substance P; D015287:Neurokinin B