The interaction of the NK₁ receptor antagonist CP‐96,345 with L‐type calcium channels and its functional consequences

Abstract

1 We investigated the effects of the non-peptide NK1 receptor antagonist, CP-96,345, its inactive enantiomer CP-96,344, and the racemic mixture ( ± )-CP-96,345, on the binding of [3H]-nimodipine and [3H]-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, agonists [Sar9, Met(02)"]SP and substance P-methyl ester that was apparently competitive in nature (pKB 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, receptors are not present. The functional effect that may be observed in integrated models will be a consequence of either property, or be a composite effect of NK, receptor antagonism and L-channel blockade.

Tachykinin Receptor Expression and Function in Human Esophageal Smooth Muscle

“…The advent of nonpeptide antagonists (Snider et al, 1991) allowed a more detailed examination of binding characteristics. Despite this, early compounds such as the NK1 antagonist CP-96,345 used by Huber et al (1993a,b) were later found to have confounding effects, including a strong affinity to block the L-type Ca 2ϩ channel (Guard et al, 1993). As such, in the present study, we have extended the pioneering observations by Huber et al (Huber et al, 1993a,b) by using a newer generation of selective receptor antagonists (Holzer and Holzer-Petsche, 1997a).…”

The pharmacology of GR203040, a novel, potent and selective non‐peptide tachykinin NK1 receptor antagonist

“…Several non-peptide NK, receptor antagonists, for example CP-96,345 and RP67580, have affinity for Na' and L-type Ca2+ channels (Schmidt et al, 1992;Caeser et al, 1993;Guard et al, 1993;Constantine et al, 1994;Wang et al, 1994). However, GR203040 was found to have only a weak effect on ion channels.…”

Investigation of the specificity of FK 888 as a tachykinin NK1 receptor antagonist

“…Several high affinity peptide antagonists, such as spantide II Hakanson et al, 1990; and FK 888 (Fujii et al, 1992;Hirayama et al, 1993), have also recently been described. However, non-peptide antagonists have been found to possess effects not related to tachykinin receptor antagonism (Lecci et al, 1991;Nagahisa et al, 1992;Schmidt et al, 1992;Wang & Hikanson, 1992a;Guard et al, 1993;Tamura et al, 1993), including non-specific effects on neurotransmission (Wang & HAkanson, 1992a;Wang et al, 1994) and local anaesthetic-like actions (Caeser et al, 1993;Tamura et al, 1993;Wang et al, 1994). The concentrations needed to exert these non-specific actions are approximately 10 times higher than those needed to produce blockade of tachykinin receptors (Wang & Hakanson, 1992a;Wang et al, 1994).…”