Primofiore Giampaolo, Da Settimo Federico, Taliani Sabrina, Salerno Silvia, Novellino Ettore, Greco Giovanni, Cosimelli Barbara, Besnard François, Costa Barbara, Montali Marina, Martini Claudia
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
J Med Chem. 2005 Apr 21;48(8):2936-43. doi: 10.1021/jm0408722.
A series of 2-phenyl[1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1,5(6H)-diones (PTBTs), VII, were prepared and tested at the central benzodiazepine receptor (BzR). The skeleton of these compounds was designed by formally combining the N-C=O moieties of the known BzR ligands, triazoloquinoxalines (IV) and triazinobenzimidazoles (ATBIs) (VI). Most of the PTBTs displayed submicromolar/nanomolar potency at the BzR. The 9-chloro derivatives (45-49) were generally found to be more potent than their 9-unsubstituted counterparts (37-44). Compound 45 turned out to be the most potent of the PTBTs (K(i) 2.8 nM). A subset of compounds (37, 42, 45, 49), when tested for their affinity on recombinant rat alpha1beta2gamma2, alpha2beta2gamma2, and alpha5beta3gamma2 GABA(A)/Bz receptor subtypes, showed enhanced affinities for the alpha1beta2gamma2 isoform, with compounds 45 and 49 exhibiting the highest selectivity. Moreover, compounds 45 and 49 were found to display a full agonist efficacy profile at alpha1 and alpha2 receptor subtypes, and an antagonist efficacy at alpha5-containing receptors.
制备了一系列2-苯基[1,2,3]三唑并[1,2-a][1,2,4]苯并三嗪-1,5(6H)-二酮（PTBTs），VII，并在中枢苯二氮䓬受体（BzR）上进行了测试。这些化合物的骨架是通过将已知的BzR配体三唑并喹喔啉（IV）和三嗪并苯并咪唑（ATBIs）（VI）的N-C=O部分进行形式上的组合而设计的。大多数PTBTs在BzR上表现出亚微摩尔/纳摩尔级别的效力。通常发现9-氯衍生物（45-49）比其9-未取代的对应物（37-44）更有效。化合物45是PTBTs中效力最强的（K(i) 2.8 nM）。当对一组化合物（37、42、45、49）进行重组大鼠α1β2γ2、α2β2γ2和α5β3γ2 GABA(A)/Bz受体亚型的亲和力测试时，它们对α1β2γ2亚型表现出增强的亲和力，其中化合物45和49表现出最高的选择性。此外，发现化合物45和49在α1和α2受体亚型上表现出完全激动剂的功效特征，而在含α-5的受体上表现出拮抗剂的功效。
