5-HT₄ receptor antagonist affinities of SB207710, SB205008, and SB203186 in the human colon, rat oesophagus, and guinea-pig ileum peristaltic reflex

Abstract

Functional 5-HT₄ receptors have been reported to be present in numerous isolated tissue preparations including the rat oesophagus, guineapig ileum, and human colon. The pharmacological properties of the novel, potent and selective 5-HT₄ receptor antagonists SB203186 (1-piperidinyl)ethyl 1H-indole 3-carboxylate, SB205008 (1-butyl-1-methyl4-piperidinylmethyl)-8-amino-7-chloro-1,4-benzodioxan-5-carboxylate iodide, and SB207710 (1-butyl-4-piperidinylmethyl)-8-amino-7-iodo-1,4 benzodioxan-5-carboxylate) were studied in these tissues. The nature of antagonism of the 5-HT-induced effects was investigated on the above isolated tissue preparations.

5-HT produced its effect with the following EC₅₀ values: 400 ± 0.4 nM (rat oesophagus, n = 20), 154 ±14 nM (guinea-pig ileum, n = 9) and 144 ± 0.1 nM (hu man colon, n = 9). SB207710 (0.03–1 nM), SB205008 (1.0–10 nM), and SB203186 (10–100 nM) antagonised the 5-HT₄ receptor-mediated relaxations of the carbachol-contracted rat isolated oesophagus against 5-HT with pK_B values of 10.9 ± 0.1, 9.5 ± 0.1, and 9.0 ± 0.1 respectively without effecting the maximum response. On the guinea-pig ileum peristaltic reflex preparation, SB207710 (0.01–1 nM) did not modify the reflex but it behaved as an antagonist of the 5-HT-induced facilitation with a pA₂ value of 9.9 ± 0.2. The agonists DAU 6236 (endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl 2,3-dihydro-3-ethyl-2-oxo-1H-benzimidazole-1-carboxylate hydrochloride) at 2 μM, and SC 53116 (1-S,8-S)-4-amino-5-chloro-N- [(hexahydro-1H-pyrrolizin-1-yl)methyl]-2-methoxy-benzamide hydrochloride at 500 nM facilitated the peristaltic reflex. SB207710 (0.25–5 nM), SB205008 (1–100 nM) and SB203186 (10–1000 nM) failed to modify the spontaneous activity of the circular muscle of the human colon, but caused parallel, dextral shifts in the concentration-effect curves to 5-HT with apparent pK_B values of 10.0 ± 0.3 (0.25 nM), 9.8 ± 0.2 (1 nM), and 8.6 ± 0.3 (10 nM) respectively. Higher concentrations of each antagonist shifted the concentration-effect curves to 5-HT to the right but this antagonism did not appear to be simple competitive. Methysergide (10 μM) and ondansetron (10 μM) increased the activity of SB207710 (5 nM) in the human colon giving rise to a 4 point (0.25, 0.5, 1,5 nM) Schild slope not significantly different from unity and a pK_B of 10.1 ± 0.1. Cocaine (30 μM). did not significantly affect the activity of SB207710.

The compounds SB207710, SB205008 and SB 203186 were shown to be high affinity 5-HT₄ receptor antagonists. SB207710 is the most potent 5-HT₄ receptor antagonist described so far and as such, is a potentially useful tool for 5-HT₄ receptor characterisation in functional studies of tissue from man and other species.