An examination of the pharmacology of two substance P antagonists and the evidence for tachykinin receptor subtypes

Abstract

1 The potencies of two tachykinin antagonists ) and Trp7'9, Leull]-SP(,II1) against four tachykinins were examined in a range of smooth muscle preparations, including guinea-pig ileum and bladder and rat colon muscularis mucosae and duodenum. 2 Parallel shifts in the log dose-response curves of all the tachykinins tested were observed in all tissues, except in the case of the guinea-pig bladder where [D-Pro4, D-Trp7'9" 0-SP(4, ] was without effect at concentrations up to 32 jaM. 3 The slopes of the Schild plots for the two antagonists did not differ significantly from unity, with the exception of [D-Pro4, D-Trp7'9"0I-SP(4 11) in the rat duodenum, which may indicate a heterogeneous receptor population in this tissue. The antagonists displayed agonist selectivity in the case of the guinea-pig ileum where log dose-response curves to substance P and physalaemin were shifted less than those to eledoisin and kassinin. 4 Rank orders of potency for eledoisin, kassinin, physalaemin and substance P in the five preparations studied allowed classification of the tissues by the predominant receptor type according to the 'SP-P' and 'SP-E' scheme.

Receptors mediating tachykinin‐induced contractile responses in guinea‐pig trachea

“…Indeed, the converse tended to occur. Tachykinin receptor antagonists have been found to exhibit agonistdependence in other tissue preparations which seem to contain only one type of tachykinin receptor (see Bailey, 1985;Bailey et al, 1986;Hall & Morton, 1991) but definitive explanation of such behaviour is awaited. In the rabbit trachea, both L-659,877 and R396 had effects qualitatively and quantitatively similar to those in guinea-pig trachea.…”

“…This question was addressed by measuring the effects of the two antagonists in tissue preparations which appear to contain tachykinin receptors of the NK2 type only and in which activity against GR64349 and NKA could be compared without the complication of needing concomitant NK1 receptor blockade. The preparations used were rabbit trachea (see Cook et al, 1990), endothelium-denuded rabbit thoracic aorta (see Results) and the rat colon muscularis mucosae (RCMM; see Bailey et al, 1986;Burcher et al, 1986).…”

“…R396 (30M) had no significant effect against contraction of the guinea-pig trachea induced by SPOMe (mean concentration-ratio (95% confidence limits) 1.2 (1.0-1.4), n = 6). ,T or the rabbit trachea (see Cook et al, 1990) and the RCMM (see Bailey et al, 1986;Burcher et al, 1986).…”

Modulation of the immune response by tachykinins

“…The use of TK antagonists, however, has proven less useful. The SP analogues which were used by many groups showed antagonistic activity for apparently more than one NK receptor, including combined NK-1 and NK-2 receptor antagonism (11,12).…”

Novel selective agonists and antagonists confirm neurokinin NK1 receptors in guinea‐pig vas deferens

“…The earlier developed neurokinin receptor antagonists, however, have been of little value for such purposes. For example, many antagonists were found to be low in potency, showed no clear neurokinin subtype selectivity, and several produced agonist-dependent potency estimates in hitherto presumed mono-receptor systems for reasons that are unclear (for discussion see, Bailey et al, 1986). Furthermore, a number of early antagonists additionally have actions not related to receptor antagonism (Karlsson et al, 1984;Lembeck et al, 1986), and several show antagonism at other receptors such as those for bombesin Jensen et al, 1984;Yachnis et al, 1984;Mizrahi et al, 1985).…”