Peglion J L, Canton H, Bervoets K, Audinot V, Brocco M, Gobert A, Le Marouille-Girardon S, Millan M J
Institut de Recherches Servier, Suresnes, France.
J Med Chem. 1995 Sep 29;38(20):4044-55. doi: 10.1021/jm00020a020.
Benzocycloalkyl and benzocycloalkenyl moities linked, directly or via an alkyl chain, to oxygen-bearing heteroarylpiperazines were synthesized, in an attempt to obtain potent and selective antagonists at postsynaptic 5-HT1A receptors. From the numerous arylpiperazines described in the literature, 1-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazine (3a) was chosen as a model of an arylpiperazine in view of its selectivity for 5-HT1A receptors versus alpha 1-, alpha 2-, and beta-adrenergic receptors, as well as dopamine D1 and D2 receptors. Two other closely-related arylpiperazines, 1-(1,5-benzodioxepin-6-yl)piperazine (3b) and 1-(benzofuran-7-yl)piperazine (3c), were also examined in this study. All compounds showed high affinity at 5-HT1A sites (8.10 < or = pKis < or = 9.35), and the majority behaved as antagonists in vivo in blocking the hypothermia induced by the 5-HT1A agonist 8-OH-DPAT in the absence of a marked effect alone at equivalent doses. An in vivo evaluation of dopamine D2 receptor antagonist properties revealed that the majority of compounds was devoid of activity at this site, in marked contrast to BMY 7378 which displayed virtually no selectivity for 5-HT1A versus dopamine D2 receptors. Moreover, six compounds of the present series, 8, 10, 11, 14, 25, and 37, showed > 10-fold selectivity in vitro for 5-HT1A versus alpha 1-adrenergic receptors. Compound 14 displayed an optimal compromise between potency (pKi = 8.75), marked antagonist activity, and selectivity toward alpha 1-adrenergic (81-fold) and dopamine D2 (195-fold) receptors. These characteristics clearly distinguish 14 from previously-reported ligands such as the postsynaptic 5-HT1A antagonist BMY 7378 and the weak partial agonist NAN 190 which, in contrast to the compounds of this series, belong to the well-exemplified class of imido derivatives of (o-methoxyphenyl)piperazines. The availability of 14 (S 15535) should facilitate the further elucidation of the functional role and potential therapeutic significance of 5-HT1A receptors.
合成了直接或通过烷基链与含氧化杂芳基哌嗪相连的苯并环烷基和苯并环烯基部分，试图获得突触后5-HT1A受体的强效和选择性拮抗剂。鉴于1-(2,3-二氢-1,4-苯并二恶英-5-基)哌嗪(3a)对5-HT1A受体相对于α1、α2和β肾上腺素能受体以及多巴胺D1和D2受体的选择性，从文献中描述的众多芳基哌嗪中选择它作为芳基哌嗪的模型。本研究还考察了另外两种密切相关的芳基哌嗪，即1-(1,5-苯并二氧杂环庚三烯-6-基)哌嗪(3b)和1-(苯并呋喃-7-基)哌嗪(3c)。所有化合物在5-HT1A位点均表现出高亲和力(8.10≤pKis≤9.35)，并且大多数化合物在体内表现为拮抗剂，在等效剂量下单独无明显作用时可阻断5-HT1A激动剂8-OH-DPAT诱导的体温过低。对多巴胺D2受体拮抗剂性质的体内评价显示，大多数化合物在该位点无活性，这与BMY 7378形成鲜明对比，BMY 7378对5-HT1A与多巴胺D2受体几乎没有选择性。此外，本系列中的6种化合物，即8、10、11、14、25和37，在体外对5-HT1A相对于α1肾上腺素能受体表现出>10倍的选择性。化合物14在效力(pKi = 8.75)、明显的拮抗剂活性以及对α1肾上腺素能(81倍)和多巴胺D2(195倍)受体的选择性之间表现出最佳平衡。这些特性清楚地将14与先前报道的配体区分开来，如突触后5-HT1A拮抗剂BMY 7378和弱部分激动剂NAN 190，与本系列化合物不同，它们属于(o-甲氧基苯基)哌嗪的亚氨基衍生物这一充分例证的类别。14(S 15535)的可得性应有助于进一步阐明5-HT1A受体的功能作用和潜在治疗意义。
