title: SR 140333, a novel, selective, and potent nonpeptide antagonist of the NK1 tachykinin receptor: characterization on the U373MG cell line.
abstract: The effects of a novel nonpeptide NK1 tachykinin receptor antagonist, SR 140333, on the functional consequences of NK1 receptor activation in a human astrocytoma cell line, U373MG, were investigated. Radioligand binding conducted with 125I-Bolton-Hunter substance P revealed a competitive inhibition by SR 140333 and its R enantiomer SR 140603 with Ki values of 0.74 and 7.40 nM, respectively. The NK1-selective agonist, [Sar9,Met(O2)11]-substance P, stimulated the formation of inositol phosphates with an EC50 of 3.8 x 10(-9) M. SR 140333 blocked the stimulatory effect of this agonist (10(-7) M) with an IC50 of 1.6 x 10(-9) M, whereas the effect of another NK1 agonist, septide (EC50 = 1.5 x 10(-8) M) was antagonized with an IC50 of 2.1 x 10(-10) M. Enhancement of [3H]taurine release by [Sar9,Met(O2)11]-substance P (EC50 = 7.4 x 10(-9) M) was also inhibited by SR 140333 with an IC50 of 1.8 x 10(-9) M. SR 140603 was 10-fold less potent than SR 140333 in inhibiting inositol monophosphate formation and [3H]taurine release. The calcium mobilization induced by [Sar9,Met(O2)11]-substance P (10(-8) M) was totally prevented by 10(-8) M SR 140333. Patch-clamp experiments showed that SR 140333 depressed the outward current evoked by 5 x 10(-8) M [Sar9, Met(O2)11]-substance P with an IC50 of 1.3 x 10(-9) M. The expression of c-fos was stimulated by [Sar9,Met(O2)11]substance P with an EC50 of 2.5 x 10(-10) M, an effect that was also inhibited by SR 140333 with an IC50 of 1.1 x 10(-9) M.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Sanofi Recherche, Montpellier, France.
authors.forename: F
authors.initials: F
authors.lastname: Oury-Donat
authors.forename: I A
authors.initials: IA
authors.lastname: Lefevre
authors.forename: O
authors.initials: O
authors.lastname: Thurneyssen
authors.forename: T
authors.initials: T
authors.lastname: Gauthier
authors.forename: A
authors.initials: A
authors.lastname: Bordey
authors.forename: P
authors.initials: P
authors.lastname: Feltz
authors.forename: X
authors.initials: X
authors.lastname: Emonds-Alt
authors.forename: G
authors.initials: G
authors.lastname: Le Fur
authors.forename: P
authors.initials: P
authors.lastname: Soubrie
mesh_terms: D001254:Astrocytoma; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D004553:Electric Conductivity; D016762:Genes, fos; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D007457:Iodine Radioisotopes; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D011812:Quinuclidines / Q000494:pharmacology*; D018040:Receptors, Neurokinin-1 / Q000502:physiology; D013237:Stereoisomerism; D013373:Substance P / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D013388:Succinimides / Q000378:metabolism; D013654:Taurine / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: C043194:Bolton Hunter reagent-substance P conjugate; D007295:Inositol Phosphates; D007457:Iodine Radioisotopes; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments; D010880:Piperidines; D011812:Quinuclidines; D018040:Receptors, Neurokinin-1; D013388:Succinimides; C062618:substance P, Sar(9)-Met(O2)(11)-; C085215:SR 140333; D013654:Taurine; D013373:Substance P; C054725:septide; D011188:Potassium; D002118:Calcium; D011761:Pyrrolidonecarboxylic Acid