Serotonin dimers: application of the bivalent ligand approach to the design of new potent and selective 5-HT(1B/1D) agonists.

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Halazy S, Perez M, Fourrier C, Pallard I, Pauwels PJ, Palmier C, John GW, Valentin JP, Bonnafous R, Martinez J

Serotonin dimers: application of the bivalent ligand approach to the design of new potent and selective 5-HT(1B/1D) agonists.

J Med Chem. 1996 Dec 6;39(25):4920-7.

PubMed ID

8960551 [ View in PubMed

]

Abstract

A series of serotonin dimers of formula 4 in which two serotonin moeities are linked together through their 5-hydroxyl residue has been prepared and evaluated as 5-HT(1B/1D) receptor agonists. Binding experiments at cloned human 5-HT(1B), 5-HT(1D), and 5-HT(1A) receptors show that all of these dimers are very potent ligands at 5-HT(1B/1D) receptors with increased binding selectivity vs the 5-HT(1A) receptor when compared to serotonin. Studies of inhibition of the forskolin-stimulated c-AMP formation mediated by the human 5-HT(1B) receptor (formerly the 5-HT(1Dbeta) receptor) demonstrate that all of these serotonin dimers behave as full agonists. Among them, the piperazide derivatives of bis-serotonin, 4g,j, were also identified as very potent agonists in contracting the New Zealand white rabbit saphenous vein (pD2 = 7.6 in each case compared to 5.8 for sumatriptan). Results analysis supports the hypothesis that the important increase in potency of the serotonin dimers can be attributed to the presence of two serotonin pharmacophores in the same molecule, while the enhanced selectivity for 5-HT(1B/1D) receptor subtypes may be due to the position of the spacer attachment to serotonin.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Sumatriptan	5-hydroxytryptamine receptor 1A	Ki (nM)	440	N/A	N/A	Details
Sumatriptan	5-hydroxytryptamine receptor 1B	Ki (nM)	23.1	N/A	N/A	Details
Sumatriptan	5-hydroxytryptamine receptor 1B	EC 50 (nM)	77	N/A	N/A	Details
Sumatriptan	5-hydroxytryptamine receptor 1D	Ki (nM)	8.5	N/A	N/A	Details