5-HT1B RECEPTOR ANTAGONIST PROPERTIES OF NOVEL ARYLPIPERAZIDE DERIVATIVES OF 1-NAPHTHYLPIPERAZINE

A new series of arylpiperazide derivatives of 1-naphthylpiperazine of general formula 4 has been prepared and evaluated as 5-HT1B antagonist s. Binding experiments at cloned human 5-HT1A, 5-HT1B, and 5-HT1D rece ptors show that these derivatives are potent and selective ligands for 5-HT1B/1D subtypes with increased binding selectivity versus the 5-HT 1A receptor when compared to 1-naphthylpiperazine (1-NP). Studies of i nhibition of the forskolin-stimulated cAMP formation mediated by the h uman 5-HT1B receptor demonstrate that the nature of the arylpiperazide substituent modulates the intrinsic activity ofthese 1-NP derivatives . Among them, alen-2-yl]oxy]-1-(4-o-tolylpiperazin-1-yl)ethanone (4a) was identified as a potent neutral 5-HT1B antagonist able to antagoniz e the inhibition of 5-HT release induced by 5-CT (5-carbamoyltryptamin e) in guinea pig hypothalamus slices. Moreover, 4a was found to potent ly antagonize the hypothermia induced by a selective 5-HT1B/1D agonist in vivo in the guinea pig following oral administration (ED50 = 0.13 mg/kg).