Synthesis and serotonergic activity of arylpiperazide derivatives of serotonin: potent agonists for 5-HT1D receptors.

A series of new arylpiperazide derivatives of serotonin has been prepared and evaluated as 5-HT 1D receptor agonists. Binding experiments at cloned human 5-HT 1Dα , 5-HT 1Dβ , and 5-HT 1A receptors show that all the compounds are very potent and selective ligands for 5-HT 1D receptor subtypes. Functional activity studies (contraction of the New Zealand white rabbit saphenous vein) demonstrate that most of the derivatives behave as full agonists. Among them, the aryl sulfonamide derivative 5q (pD 2 = 8.33 compare to 5.75 for sumatriptan) was also identified as a very potent agonist in inhibiting the forskolin-mediated cyclase coupled to 5-HT 1Dβ receptors (EC 50 = 0.52 nM).