5-HT<INF>1B</INF> Receptor Antagonist Properties of Novel Arylpiperazide Derivatives of 1-Naphthylpiperazine

A new series of arylpiperazide derivatives of 1-naphthylpiperazine of general formula<BO> 4</BO> has been prepared and evaluated as 5-HT<INF>1B</INF> antagonists. Binding experiments at cloned human 5-HT<INF>1A</INF>, 5-HT<INF>1B</INF>, and 5-HT<INF>1D</INF> receptors show that these derivatives are potent and selective ligands for 5-HT<INF>1B/1D</INF> subtypes with increased binding selectivity versus the 5-HT<INF>1A</INF> receptor when compared to 1-naphthylpiperazine (1-NP). Studies of inhibition of the forskolin-stimulated cAMP formation mediated by the human 5-HT<INF>1B</INF> receptor demonstrate that the nature of the arylpiperazide substituent modulates the intrinsic activity of these 1-NP derivatives. Among them, 2-[[8-(4-methylpiperazin-1-yl)naphthalen-2-yl]oxy]-1-(4-o-tolylpiperazin-1-yl)ethanone (<BO>4a</BO>) was identified as a potent neutral 5-HT<INF>1B</INF> antagonist able to antagonize the inhibition of 5-HT release induced by 5-CT (5-carbamoyltryptamine) in guinea pig hypothalamus slices. Moreover, <BO>4a</BO> was found to potently antagonize the hypothermia induced by a selective 5-HT<INF>1B/1D</INF> agonist in vivo in the guinea pig following oral administration (ED<INF>50</INF> = 0.13 mg/kg).