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The activity of SR 27897, a potent and selective CCK-A vs CCK-B receptor antagonist (Ki = 0.2 nM on guinea-pig pancreas vs 2000 nM on rat brain) was studied on behavioural, electrophysiological and biochemical effects induced by peripheral or central injection of CCK-8S. For comparative purposes, devazepide, a reference CCK-A receptor antagonist, was investigated in these same models. CCK-induced hypophagia and CCK-induced hypolocomotion in rats, two behavioural changes associated with the stimulation of peripheral CCK-A receptors, were dose-dependently antagonized by SR 27897 (ED50 = 0.003 and 0.002 mg/kg i.p., respectively) and devazepide (ED50 = 0.02 and 0.1 mg/kg i.p., respectively). CCK-induced decrease of cerebellar cGMP levels in mice was also reduced by SR 27897 (ED50 = 0.013 mg/kg) and by devazepide (0.084 mg/kg). The CCK-induced turning behaviour after intrastriatal injection in mice, and the potentiation of the rate suppressant activity of apomorphine on rat DA neurons, were blocked by higher doses of SR 27897 and devazepide, consistent with the probable central origin of these effects. The respective ED50s were 0.2 mg/kg i.p. for SR 27897 and 4.9 mg/kg i.p. for devazepide in the former model, while the respective minimal effective doses were 1.25 and 5 mg/kg i.p. in the latter test. In most tests the i.p./p.o. ratio for SR 27897 was near unity, suggesting a high oral bioavailability of the compound. Taken together, these findings support the notion that SR 27897 behaves as a potent CCK-A antagonist able to cross the blood brain barrier.

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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