Mascia Maria Paola, Ledda Giovanni, Orrù Alessandro, Marongiu Alessandro, Loriga Giovanni, Maciocco Elisabetta, Biggio Giovanni, Ruiu Stefania
CNR - Institute of Neuroscience, Cittadella Universitaria, 09042 Monserrato, Italy.
Department of Life and Environmental Science, Center of Excellence for the Neurobiology of Dependence, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Italy.
Eur J Pharmacol. 2014 Jun 15;733:1-6. doi: 10.1016/j.ejphar.2014.03.039. Epub 2014 Apr 1.
Several aryl pyrazoles characterized by a different molecular structure (flexible vs constrained), but chemically related to rimonabant and AM251, were tested for their ability to modulate the function of recombinant α1β2γ2L GABAA receptors expressed in Xenopus laevis oocytes. The effects of 6Bio-R, 14Bio-R, NESS 0327, GP1a and GP2a (0.3-30 μM) were evaluated using a two-electrode voltage-clamp technique. 6Bio-R and 14Bio-R potentiated GABA-evoked Cl(-) currents. NESS 0327, GP1a and GP2a did not affect the GABAA receptor function, but they acted as antagonists of 6Bio-R. Moreover, NESS 0327 inhibited the potentiation of the GABAA receptor function induced by rimonabant. The benzodiazepine site seems to participate in the action of these compounds. In fact, flumazenil antagonized the potentiation of the GABAA receptor induced by 6Bio-R, and NESS 0327 reduced the action of lorazepam and zolpidem. On the contrary, NESS 0327 did not antagonize the action of "classic" GABAergic modulators (propanol, anesthetics, barbiturates or steroids). In α1β2 receptors 6Bio-R potentiated the GABAergic function, but flumazenil was still able to antagonize the potentiation induced by 6Bio-R. Aryl pyrazole derivatives activity at the GABAA receptor depends on their molecular structure. These compounds bind to both an αβγ binding site, and to an α/β site which do not require the γ subunit and that may provide structural leads for drugs with potential anticonvulsant effects.
测试了几种具有不同分子结构（柔性与受限型）但在化学上与利莫那班和AM251相关的芳基吡唑，以评估它们调节非洲爪蟾卵母细胞中表达的重组α1β2γ2L GABAA受体功能的能力。使用双电极电压钳技术评估了6Bio-R、14Bio-R、NESS 0327、GP1a和GP2a（0.3 - 30 μM）的作用。6Bio-R和14Bio-R增强了GABA诱发的Cl(-)电流。NESS 0327、GP1a和GP2a不影响GABAA受体功能，但它们作为6Bio-R的拮抗剂起作用。此外，NESS 0327抑制了利莫那班诱导的GABAA受体功能增强。苯二氮䓬位点似乎参与了这些化合物的作用。事实上，氟马西尼拮抗了6Bio-R诱导的GABAA受体增强作用，NESS 0327降低了劳拉西泮和唑吡坦的作用。相反，NESS 0327不拮抗“经典”GABA能调节剂（丙醇、麻醉剂、巴比妥类药物或类固醇）的作用。在α1β2受体中，6Bio-R增强了GABA能功能，但氟马西尼仍能拮抗6Bio-R诱导的增强作用。芳基吡唑衍生物在GABAA受体上的活性取决于它们的分子结构。这些化合物既能结合αβγ结合位点，也能结合不需要γ亚基的α/β位点，这可能为具有潜在抗惊厥作用的药物提供结构线索。
