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) radioliga nd [H-3]GR 113808 was identified in pig caudate nucleus and characteri zed by serotonin subtype selective drugs. Binding was inhibited by ser otonin and by synthetic indoles, benzamides and benzimidazolones known to characterize the 5-HT(4)R in functional tests. Rank order of poten cy 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 > DA U 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 agoni sts was: SC 53116 (K-i, 21 nM) > BIMU 1 > cisapride > BIMU 8 > seroton in > renzapride > S-zacopride > metoclopramide > R-zacopride > 5-metho xytryptamine >> 5-carboxamiolotryptamine. BIMU 8, renzapride, metoclop ramide and the zacopride enantiomers gave shallow competition curves. The agonists were substantially less selective than the antagonists wi th respect to the 5-HT(3)R. With only two exceptions, SCH 23390 and me tergoline, 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 affinit ies of compounds for 5-HT(4)R in caudata of pigs, guinea pigs and huma ns were found suggesting no difference among mammalian species.