SR 140333, a Novel, Selective, and Potent Nonpeptide Antagonist of the NK1 Tachykinin Receptor: Characterization on the U373MG Cell Line
- 1 April 1994
- journal article
- Published by Wiley in Journal of Neurochemistry
- Vol. 62 (4), 1399-1407
- https://doi.org/10.1046/j.1471-4159.1994.62041399.x
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)Keywords
This publication has 40 references indexed in Scilit:
- Functional characterization of neurokinin‐1 receptors on human U373MG astrocytoma cellsGlia, 1992
- Tachykinin receptor types: Classification and membrane signalling mechanismsNeurochemistry International, 1991
- A Potent Nonpeptide Antagonist of the Substance P (NK 1 ) ReceptorScience, 1991
- Tachykinin Receptors of the NK1 Type (Substance P) Coupled Positively to Phospholipase C on Cortical Astrocytes from the Newborn Mouse in Primary CultureJournal of Neurochemistry, 1989
- Calcium as a modulator of the immediate-early gene cascade in neuronsCell Calcium, 1988
- Different tachykinin receptor subtypes are coupled to the phosphoinositide or cyclic AMP signal transduction pathways in rat submandibular cellsFEBS Letters, 1988
- The c-fos serum response element responds to protein kinase C-dependent and -independent signals but not to cyclic AMP.Genes & Development, 1988
- Mammalian tachykinin-induced hydrolysis of inositol phospholipids in rat brain slicesBiochemical and Biophysical Research Communications, 1985
- Correlation between inositol phospholipid hydrolysis and substance P receptors in rat CNSNature, 1984