title: Identification of serotonin 5-HT4 recognition sites in the porcine caudate nucleus by radioligand binding.
abstract: Specific binding for the serotonin 5-HT4 receptor (5-HT4R) radioligand [3H]GR 113808 was identified in pig caudate nucleus and characterized by serotonin subtype selective drugs. Binding was inhibited by serotonin and by synthetic indoles, benzamides and benzimidazolones known to characterize the 5-HT4R in functional tests. Rank order of potency of 5-HT4R antagonists was: GR 125487 (Ki, 0.19 nM) > GR 113808 >> SC 53606 > SDZ 205,557 > RS 235971/190 > DAU 6285 > tropisetron > DAU 6215. GR 125487 and GR 113808 were highly selective with respect to the 5-HT3 receptor (5-HT3R). Rank order of potency of 5-HT4R agonists was: SC 53116 (Ki, 21 nM) > BIMU 1 > cisapride > BIMU 8 > serotonin > renzapride > S-zacopride > metoclopramide > R-zacopride > 5-methoxytryptamine >> 5-carboxamidotryptamine. BIMU 8, renzapride, metoclopramide and the zacopride enantiomers gave shallow competition curves. The agonists were substantially less selective than the antagonists with respect to the 5-HT3R. With only two exceptions, SCH 23390 and metergoline, which bound with sub-microM affinity to the 5-HT4R, binding was not inhibited by compounds selective for other G-protein-coupled or channel-gated receptors. Highly significant correlations in affinities of compounds for 5-HT4R in caudata of pigs, guinea pigs and humans were found suggesting no difference among mammalian species.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, Boehringer Ingelheim Italia, Milan, Italy.
authors.forename: G B
authors.initials: GB
authors.lastname: Schiavi
authors.forename: S
authors.initials: S
authors.lastname: Brunet
authors.forename: C A
authors.initials: CA
authors.lastname: Rizzi
authors.forename: H
authors.initials: H
authors.lastname: Ladinsky
mesh_terms: D000818:Animals; D001562:Benzimidazoles; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002421:Caudate Nucleus / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism; D005910:Glioma / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D009447:Neuroblastoma / Q000378:metabolism; D011869:Radioligand Assay; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000493:pharmacokinetics; D017366:Serotonin Receptor Agonists / Q000493:pharmacokinetics; D013552:Swine; D014363:Tryptamines / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured
chemical_list: D001562:Benzimidazoles; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; C070191:itasetron; D019204:GTP-Binding Proteins