IDENTIFICATION OF SEROTONIN 5-HT4, RECOGNITION SITES IN THE PORCINE CAUDATE-NUCLEUS BY RADIOLIGAND BINDING

Specific binding for the serotonin 5-HT4 receptor (5-HT(4)R) radioligand [H-3]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-HT(4)R in functional tests. Rank order of potency of 5-HT(4)R antagonists was: GR 125487 (K-i, 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-HT(3)R). Rank order of potency of 5-HT(4)R agonists was: SC 53116 (K-i, 21 nM) > BIMU 1 > cisapride > BIMU 8 > serotonin > renzapride > S-zacopride > metoclopramide > R-zacopride > 5-methoxytryptamine >> 5-carboxamiolotryptamine. 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-HT(3)R. With only two exceptions, SCH 23390 and metergoline, which bound with sub-mu M affinity to the 5-HT(4)R, 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-HT(4)R in caudata of pigs, guinea pigs and humans were found suggesting no difference among mammalian species.