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The effects of a novel nonpeptide NK1 tachy‐kinin 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 125l‐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 × 10−9M. SR 140333 blocked the stimulatory effect of this agonist (10−7M) with an IC50 of 1.6 × 10−9M,whereas the effect of another NK1 agonist, septide (EC50= 1.5 × 10−8M)was antagonized with an IC50 of 2.1 × 10−10M.Enhancement of [3H]taurine release by [Sar9,Met(O2)11]‐substance P (EC50= 7.4 × 10−9M) was also inhibited by SR 140333 with an IC50 of 1.8 × 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 (10−8M) was totally prevented by 10−8MSR 140333. Patchclamp experiments showed that SR 140333 depressed the outward current evoked by 5 × 10−8M [Sar9, Met(O2)11]‐substance P with an IC50 of 1.3 × 10−9M. The expression of c‐fos was stimulated by [Sar9,Met(O2)11]‐substance P with an EC50 of 2.5 × 10−10M, an effect that was also inhibited by SR 140333 with an IC50 of 1.1 × 10−9M. The present results illustrate the sequential events of the response elicited by NK1 agonists, which were antagonized by SR 140333, demonstrating its powerful NK1 antagonist activity on a functional basis.

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