| Abstract
| - A new series of arylpiperazide derivatives of 1-naphthylpiperazineof general formula 4 hasbeen prepared and evaluated as 5-HT1B antagonists.Binding experiments at cloned human5-HT1A, 5-HT1B, and 5-HT1Dreceptors show that these derivatives are potent andselectiveligands for 5-HT1B/1D subtypes with increased bindingselectivity versus the 5-HT1A receptorwhen compared to 1-naphthylpiperazine (1-NP). Studies ofinhibition of the forskolin-stimulatedcAMP formation mediated by the human 5-HT1B receptordemonstrate that the nature of thearylpiperazide substituent modulates the intrinsic activity of these1-NP derivatives. Amongthem,2-[[8-(4-methylpiperazin-1-yl)naphthalen-2-yl]oxy]-1-(4-o-tolylpiperazin-1-yl)ethanone(4a)was identified as a potent neutral 5-HT1B antagonist ableto antagonize the inhibition of 5-HTrelease induced by 5-CT (5-carbamoyltryptamine) in guinea pighypothalamus slices. Moreover,4a was found to potently antagonize the hypothermia inducedby a selective 5-HT1B/1D agonistin vivo in the guinea pig following oraladministration (ED50 = 0.13 mg/kg).
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