作为α1和5-HT1A受体配体的1,2,4-苯并噻二嗪衍生物

1,2,4-Benzothiadiazine derivatives as alpha1 and 5-HT1A receptor ligands.

作者信息

Tait Annalisa, Luppi Amedeo, Franchini Silvia, Preziosi Elisa, Parenti Carlo, Buccioni Michela, Marucci Gabriella, Leonardi Amedeo, Poggesi Elena, Brasili Livio

机构信息

Dipartimento di Scienze Farmaceutiche, Università degli Studi di Modena e Reggio Emilia, Via Campi 183, 41100 Modena, Italy.

出版信息

Bioorg Med Chem Lett. 2005 Feb 15;15(4):1185-8. doi: 10.1016/j.bmcl.2004.12.004.

DOI:10.1016/j.bmcl.2004.12.004

PMID:15686938

Abstract

A series of new 1,2,4-benzothiadiazine derivatives with an arylpiperazine mojety linked at position 3 of the heterocyclic ring were synthesized and assessed for their pharmacological profiles at alpha(1)-adrenoceptor subtypes (alpha(1A), alpha(1B) and alpha(1D)) by functional experiments and by in vitro binding studies at human cloned 5-HT(1A) receptor. Compound 1 was identified as a novel alpha(1D) antagonist (pK(b)alpha(1D)=7.59; alpha(1D)/alpha(1A)>389; alpha(1D)/alpha(1B)=135) with high selectivity over 5-HT(1A) receptor (5-HT(1A)/alpha(1D)<0.01), while compound 6, a 3,4-dihydro-derivative, was characterized as a novel 5-HT(1A) receptor ligand, highly selective over alpha(1D)-adrenoceptor subtype (pK(i)5-HT(1A)=8.04; 5-HT(1A)/alpha(1D)=1096). Further pharmacological studies demonstrated that 6 is a partial agonist at 5-HT(1A) receptor (E(max)=23, pD(2)=6.92).

摘要

合成了一系列在杂环的3位连接有芳基哌嗪基团的新型1,2,4-苯并噻二嗪衍生物，并通过功能实验以及在人克隆5-HT(1A)受体上的体外结合研究，评估了它们对α(1)-肾上腺素能受体亚型（α(1A)、α(1B)和α(1D)）的药理学特征。化合物1被鉴定为一种新型α(1D)拮抗剂（pK(b)α(1D)=7.59；α(1D)/α(1A)>389；α(1D)/α(1B)=135），对5-HT(1A)受体具有高选择性（5-HT(1A)/α(1D)<0.01），而化合物6，一种3,4-二氢衍生物，被表征为一种新型5-HT(1A)受体配体，对α(1D)-肾上腺素能受体亚型具有高选择性（pK(i)5-HT(1A)=8.04；5-HT(1A)/α(1D)=1096）。进一步的药理学研究表明，6是5-HT(1A)受体的部分激动剂（E(max)=23，pD(2)=6.92）。