HIGHER POTENCY OF RP-67580, IN THE MOUSE AND THE RAT COMPARED WITH OTHER NONPEPTIDE AND PEPTIDE TACHYKININ NK1 ANTAGONISTS

1 This study was undertaken to compare the potency and selectivity of the nonpeptide (RP 67580, ( +/- )-CP-96,345 and its chloro-derivative [( +/- )-cis-3-(2-chlorobenzylamino)-2-benzhydrylquinuclidine] (CP-Cl)) and peptide (GR 71,251 and spantide) neurokinin1 (NK1) antagonists in mouse and rat preparations. 2 Among the NK1 antagonists tested, RP 67580 was the most potent in inhibiting the specific binding of [I-125]-Bolton Hunter substance P ([I-125]-BHSP) to crude synaptosomes from the rat brain (K(i): 2.9 nm). ( +/- )-CP-96,345 was about ten fold less potent (K(i): 31 nm) than RP 67580 while other compounds exhibited even less affinity. 3 All NK1 antagonists inhibit competitively the activation of phospholipase C by [Pro9]substance P ([Pro9]SP) in cultured cortical astrocytes from the newborn mouse, a preparation rich in NK1 receptors but devoid of NK2 and NK3 receptors. pA2 values for the most potent compounds, RP 67580 and ( +/- )-CP-96,345, were 8.28 and 7.08 respectively. When used alone, all antagonists showed some agonist activity at 10(-5) m, except spantide which was already effective at 10(-6) m. 4 An excellent correlation was found between the potency of the NK1 antagonists in blocking the stimulation by [Pro9]SP of phosphoinositide breakdown in cortical astrocytes and in inhibiting [I-125]-BHSP specific binding to rat brain synaptosomes. 5 As shown on single cells by use of the Indo-I microfluorometric method, RP 67580 (10(-7) m) prevented reversibly the elevation of cytosolic calcium concentration induced by [Pro9]SP (10(-8) m) in cultured cortical astrocytes. 6 Several experiments indicated that the antagonists were highly selective for NK1 receptors. RP 67580 did not modify the noradrenaline-evoked activation of phospholipase C in cortical astrocytes; when used at 10(-5) m all antagonists had no or only little affinity for NK2 or NK3 binding sites and did not block the NKA (10(-8) m)-induced activation of phospholipase C in the hamster urinary bladder (a selective NK2 test). 7 In conclusion, RP 67580 appears to be a potent NK1 antagonist in the mouse and the rat. Results obtained with ( +/- )-CP-96,345 confirm the lower potency of this compound in these two species when compared with reported data obtained in the guinea-pig or man.