SDZ 205-557, a selective, surmountable antagonist for 5-HT4 receptors in the isolated guinea pig ileum

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Abstract
A selective antagonist for the recently characterized 5-HT4-receptor is lacking. The only surmountable antagonist available, ICS 205-930, is a weak antagonist and is far more potent at 5-HT3-than at 5-HT4 receptors. In this paper, SDZ 205-557 (2-methoxy-4-amino-5-chloro-benzoic acid 2-(diethylamino) ethyl ester) is characterized as the first potent, selective and surmountable antagonist at 5-HT4 receptors in the isolated guinea pig ileum. SDZ 205-557 was investigated in the non-stimulated and in the field-stimulated guinea pig ileum longitudinal muscle preparation for its affinity for 5-HT4-, 5-HT3-, muscarine-, nicotine- and histamine H1 receptors. The affinity for 5-HT1-, 5-HT2-, α1-, α2- and opiate (μ) receptors was determined by binding assays. SDZ 205-557 was devoid of substantial affinity (pKD values below 5.6) for all receptors investigated except for 5-HT3- and 5-HT4 receptors. At these two receptors, SDZ 205-557 acted as an antagonist without measurable intrinsic activity. At the 5-HT4 receptors of the non-stimulated guinea pig ileum, responses to 5-HT and 5-methoxytryptamine were antagonized by SDZ 205-557 with identical pA2 values of 7.4. The effect of renzapride was also blocked with no significant change in the maximum response; Schild analysis, however, revealed that the interaction was not competitive with an “apparent” pA2 value of 7.6. A pA2 of 6.8 was obtained using zacopride as a contractile agent; this value differed significantly from 7.4, the value obtained for 5-HT and 5-methoxytryptamine. The effects of metoclopramide were inhibited non-competitively with a pD2' value of 5.4. 5-HT4 receptor mediated effects in the field-stimulated guinea pig ileum were antagonized in a similar way by SDZ 205-557. The resulting pA2 values were not significantly different from those obtained in the non-stimulated preparation. In the non-stimulated preparation, contractions induced by 5-HT and 2-methyl-5-HT via activation of 5-HT3 receptors were antagonized by SDZ 205-557 only at concentrations of 10−6 mol/l and above yielding pA2 values of 5.6 and 5.9, respectively, which were considerably lower than those obtained for the blockade of 5-HT4 receptors. At concentrations greater than 10−6 mol/l, SDZ 205-557 caused a significant reduction of the maximum responses, indicating non-competitive antagonism. It is concluded that SDZ 205-557 is a potent, selective and surmountable antagonist at 5-HT4 receptors in the isolated guinea pig ileum, and is a more practical tool for the characterization of 5-HT4 receptors than ICS 205-930.