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: F Oury-Donat, I A Lefevre, O Thurneyssen, T Gauthier, A Bordey, P Feltz, X Emonds-Alt, G Le Fur, P Soubrie
• Journal: Journal of neurochemistry (J Neurochem) Vol. 62 Issue 4 Pg. 1399-407 (Apr 1994) ISSN: 0022-3042 [Print] England
• PMID: 7510780 (Publication Type: Journal Article)

Chemical References

• Bolton Hunter reagent-substance P conjugate
• Inositol Phosphates
• Iodine Radioisotopes
• Neurokinin-1 Receptor Antagonists
• Peptide Fragments
• Piperidines
• Quinuclidines
• Receptors, Neurokinin-1
• Succinimides
• substance P, Sar(9)-Met(O2)(11)-
• SR 140333
• Taurine
• Substance P
• septide
• Potassium
• Calcium
• Pyrrolidonecarboxylic Acid

Topics

• Astrocytoma
• Binding, Competitive
• Calcium (metabolism)
• Electric Conductivity
• Genes, fos
• Humans
• Inositol Phosphates (metabolism)
• Iodine Radioisotopes
• Neurokinin-1 Receptor Antagonists
• Peptide Fragments (pharmacology)
• Piperidines (pharmacology)
• Potassium (metabolism)
• Pyrrolidonecarboxylic Acid (analogs & derivatives)
• Quinuclidines (pharmacology)
• Receptors, Neurokinin-1 (physiology)
• Stereoisomerism
• Substance P (analogs & derivatives, metabolism, pharmacology)
• Succinimides (metabolism)
• Taurine (metabolism)
• Transcription, Genetic (drug effects)
• Tumor Cells, Cultured