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The interaction of the NK 1 receptor antagonist CP‐96,345 with L‐type calcium channels and its functional consequences
Author(s) -
Guard S.,
Boyle S.J.,
Tang K.W.,
Watling K.J.,
McKnight A.T.,
Woodruff G.N.
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.tb13821.x
Subject(s) - diltiazem , nimodipine , antagonism , antagonist , ileum , chemistry , receptor , muscarinic acetylcholine receptor , medicine , calcium , endocrinology , pharmacology , biology , biochemistry
1 We investigated the effects of the non‐peptide NK 1 receptor antagonist, CP‐96,345, its inactive enantiomer CP‐96,344, and the racemic mixture (±)‐CP‐96,345, on the binding of [ 3 H]‐nimodipine and [ 3 H]‐diltiazem to L‐type calcium channels in rat cerebral cortex membranes. In isolated peripheral tissues containing tachykinin receptors, the effects of (±)‐CP‐96,345 have been compared with those of diltiazem. 2 In guinea‐pig trachea, (±)‐CP‐96,345 produced antagonism of responses to the selective NK 1 agonists [Sar 9 , Met(O 2 ) 11 ]SP and substance P‐methyl ester that was apparently competitive in nature (p K B 7.0–7.5), while in guinea‐pig ileum the antagonism was not surmountable. 3 The reduction of maximum responses by (±)‐CP‐96,345 in the guinea‐pig ileum was not selective; it was obtained with muscarinic agonists and other agents, and was also observed in the portal vein of the rat where NK 1 receptors are not present. 4 The tissue‐specific reduction of maximum responses by (±)‐CP‐96,345 in ileum was reproduced by diltiazem. 5 (±)‐CP‐96,345 produced a concentration‐dependent enhancement of [ 3 H]‐nimodipine binding to rat cerebral cortex membranes with a maximal stimulation of 186 ± 29% above control (EC 50 83.2 n m ). Scatchard analysis revealed that (±)‐CP‐96,345 increased the affinity of [ 3 H]‐nimodipine for its binding sites without affecting B max (control: K D = 0.32 n m ; with 100 n m (±)‐CP‐96,345: K D = 0.074 n m ). 6 CP‐96,345, CP‐96,344, and the racemate all inhibited [ 3 H]‐diltiazem binding in rat cerebral cortex membranes with K i values of 22.5 n m , 34.5 n m and 29.9 n m respectively; a similar value was obtained for diltiazem itself (33.6 n m ). In comparison, CP‐96,345 and (±)‐CP‐96,345 inhibited the binding of [ 125 I]‐Bolton‐Hunter‐conjugated substance P in this tissue with K i values of 59.6 n m and 82.0 n m respectively, while CP‐96,344 had no measurable affinity (IC 50 > 10 μ m ). 7 Substance P and a range of ligands selective for NK 1 , NK 2 , or NK 3 receptors had no significant effect at 10 μ m on either [ 3 H]‐diltiazem or [ 3 H]‐nimodipine binding. 8 The results indicate that in addition to possessing affinity for the NK 1 receptor, the non‐peptide antagonist, CP‐96,345, displays high affinity for [ 3 H]‐diltiazem binding sites on L‐type calcium channels. The functional effect that may be observed in integrated models will be a consequence of either property, or be a composite effect of NK 1 receptor antagonism and L‐channel blockade.