title: 5-HT1B receptor antagonist properties of novel arylpiperazide derivatives of 1-naphthylpiperazine.
abstract: A new series of arylpiperazide derivatives of 1-naphthylpiperazine of general formula 4 has been prepared and evaluated as 5-HT1B antagonists. Binding experiments at cloned human 5-HT1A, 5-HT1B, and 5-HT1D receptors show that these derivatives are potent and selective ligands for 5-HT1B/1D subtypes with increased binding selectivity versus the 5-HT1A receptor when compared to 1-naphthylpiperazine (1-NP). Studies of inhibition of the forskolin-stimulated cAMP formation mediated by the human 5-HT1B 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 (4a) was identified as a potent neutral 5-HT1B antagonist able to antagonize the inhibition of 5-HT release induced by 5-CT (5-carbamoyltryptamine) in guinea pig hypothalamus slices. Moreover, 4a was found to potently 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).
authors.affiliation: Department of Cellular and Molecular Biology, Centre de Recherche Pierre FABRE, Castres, France.
authors.forename: C
authors.initials: C
authors.lastname: Jorand-Lebrun
authors.forename: P J
authors.initials: PJ
authors.lastname: Pauwels
authors.forename: C
authors.initials: C
authors.lastname: Palmier
authors.forename: C
authors.initials: C
authors.lastname: Moret
authors.forename: P
authors.initials: P
authors.lastname: Chopin
authors.forename: M
authors.initials: M
authors.lastname: Perez
authors.forename: M
authors.initials: M
authors.lastname: Marien
authors.forename: S
authors.initials: S
authors.lastname: Halazy
mesh_terms: D000818:Animals; D016466:CHO Cells / Q000378:metabolism / Q000648:ultrastructure; D019556:COS Cells / Q000378:metabolism / Q000648:ultrastructure; D006224:Cricetinae; D015195:Drug Design; D006168:Guinea Pigs; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D010879:Piperazines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C470302:HTR1B protein, human; D010879:Piperazines; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C048241:1-(1-naphthyl)piperazine