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Higher potency of RP 67580, in the mouse and the rat compared with other nonpeptide and peptide tachykinin NK 1 antagonists
Author(s) -
Beaujouan JeanClaude,
Heuillet Edith,
Petitet François,
Saffroy Monique,
Torrens Yvette,
Glowinski Jacques
Publication year - 1993
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1993.tb12880.x
Subject(s) - substance p , potency , tachykinin receptor , agonist , receptor , medicine , antagonist , stimulation , endocrinology , biology , neuropeptide , biochemistry , in vitro
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‐C1)) and peptide (GR 71,251 and spantide) neurokinin 1 (NK 1 ) antagonists in mouse and rat preparations. 2 Among the NK 1 antagonists tested, RP 67580 was the most potent in inhibiting the specific binding of [ 125 I]‐Bolton Hunter substance P ([ 125 I]‐BHSP) to crude synaptosomes from the rat brain ( K i : 2.9 n m ). (±)‐CP‐96,345 was about ten fold less potent ( K i : 31 n m ) than RP 67580 while other compounds exhibited even less affinity. 3 All NK 1 antagonists inhibit competitively the activation of phospholipase C by [Pro 9 ]substance P ([Pro 9 ]SP) in cultured cortical astrocytes from the newborn mouse, a preparation rich in NK 1 receptors but devoid of NK 2 and NK 3 receptors. pA 2 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 NK 1 antagonists in blocking the stimulation by [Pro 9 ]SP of phosphoinositide breakdown in cortical astrocytes and in inhibiting [ 125 I]‐BHSP specific binding to rat brain synaptosomes. 5 As shown on single cells by use of the Indo‐1 microfluorometric method, RP 67580 (10 −7 m ) prevented reversibly the elevation of cytosolic calcium concentration induced by [Pro 9 ]SP (10 −8 m ) in cultured cortical astrocytes. 6 Several experiments indicated that the antagonists were highly selective for NK 1 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 NK 2 or NK 3 binding sites and did not block the NKA (10 −8 m )‐induced activation of phospholipase C in the hamster urinary bladder (a selective NK 2 test). 7 In conclusion, RP 67580 appears to be a potent NK 1 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.