Receptors for 5-hydroxytryptamine (5-HT) of the 5-HT4 type were investigated in the intestinal tract and the striatum in guinea-pig, in binding studies using the 5-HT4 radioligand, [3H]GR113808. In the intestinal tract, specific binding was observed in preparations of the longitudinal muscle with the myenteric plexus (LMMPs) but not in the whole tissue. Saturable binding of [3H]GR113808 was demonstrated (striatum: Kd = 0.054 +/- 0.002 nM, Bmax = 90.25 +/- 10.44 fmol/mg protein, LMMPs of ileum: Kd = 0.077 +/- 0.016 nM, Bmax = 11.95 +/- 3.24 fmol/mg protein). Selective 5-HT4 receptor agonists and antagonists inhibited binding of [3H]GR113808 with high affinities in LMMPs of the ilcum and which correlated well with their actions on the striatum (r = 0.98), as indicated by the rank order of displacement potencies: SDZ205-557 > LY297524 > cisapride = BIMU8 > 5-HT > mosapride > renzapride > 5-hydroxy-N-methyltryptamine(5-HMT) > (+/-) zacopride > alpha-methyl-5-hydroxytryptamine (alpha-M-5-HT) > 5-methyltryptamine(5-MT) > 5-carboxamidotryptamine (5-CT). The number of binding sites of [3H]GR113808 in the intestine was significantly smaller than that in the brain. In the intestine, a larger number of binding sites was noted in the upper part of the intestine, the rank order being duodenum > jcjunum > ilcum > > colon > rectum. Such data are relevant regarding the potential use of the 5-HT4 receptor ligand to modify motility and secretion in the intestine.

01 Mar 1992·Journal of Medicinal ChemistryQ1 · MEDICINE

Novel 5-HT3 antagonists: indol-3-ylspiro(azabicycloalkane-3,5'(4'H)oxazoles)

Q1 · MEDICINE

Article

Author: Beer, M. ; Swain, C. J. ; Saunders, J. ; Kneen, C. ; Moseley, J. ; Baker, R. ; Stevenson, G. I. ; Herbert, R. ; Seward, E. M.

The synthesis and biochemical evaluation of a series of spirofused indole oxazoline 5-HT3 antagonists is described in which the oxazoline ring acts as a bioisosteric replacement for esters and amides. The effect of substitution about the indole ring has shown the steric limitations of the aromatic binding site. Incorporation of a variety of azabicyclic systems within the rigid spirofused framework has allowed the definition of a binding model which incorporates a number of known antagonists and agonists. In this model steric constraints limit substitution around the indole ring although there is some bulk tolerance at the 1- and 2-positions. The importance of constraining the basic nitrogen within an azabicyclic system is underlined by comparison with the monocyclic piperidine. The highest affinity was observed for those compounds in which the basic nitrogen occupies a bridgehead position, the most potent analogue in this group being the azabicyclic [3.3.1] system (pIC50 = 8.95), suggesting lipophilic interactions may play a role in increasing affinity. A suggested model for agonist binding is included in which the basic nitrogens are superimposed and the 5-hydroxyl group of 5-HT is superimposed on the H-bond-accepting atom of the heterocyclic linking group.

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Vomiting	Discovery	United States	Eli Lilly & Co.	-

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