title: SDZ 205-557, a selective, surmountable antagonist for 5-HT4 receptors in the isolated guinea pig ileum.
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-, alpha 1-, alpha 2- and opiate (mu) 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.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Preclinical Research (386/543), SANDOZ Pharma Ltd., Basel, Switzerland.
authors.forename: K H
authors.initials: KH
authors.lastname: Buchheit
authors.forename: R
authors.initials: R
authors.lastname: Gamse
authors.forename: H J
authors.initials: HJ
authors.lastname: Pfannkuche
mesh_terms: D010129:4-Aminobenzoic Acid / Q000494:pharmacology; D000818:Animals; D004558:Electric Stimulation; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D011869:Radioligand Assay; D012702:Serotonin Antagonists / Q000494:pharmacology; D000077526:Tropisetron; D062366:para-Aminobenzoates
chemical_list: D007211:Indoles; D012702:Serotonin Antagonists; D062366:para-Aminobenzoates; C072790:2-methoxy-4-amino-5-chlorobenzoic acid 2-(diethylamino)ethyl ester; D000077526:Tropisetron; D010129:4-Aminobenzoic Acid