Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, I-53100 Siena, SI, Italy.
Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, I-53100 Siena, SI, Italy.
Bioorg Med Chem Lett. 2020 Sep 15;30(18):127443. doi: 10.1016/j.bmcl.2020.127443. Epub 2020 Jul 28.
Positive allosteric modulators (PAMs) of GABA receptor represent an interesting alternative to receptor agonists such as baclofen, as they act on the receptor in a more physiological way and thus are devoid of the side effects typically exerted by the agonists. Based on our interest in the identification of new GABA receptor PAMs, we followed a merging approach to design new chemotypes starting from selected active compounds, such as GS39783, rac-BHFF, and BHF177, and we ended up with the synthesis of four different classes of compounds. The new compounds were tested alone or in the presence of 10 µM GABA using [S]GTPγS binding assay to assess their functionality at the receptor. Unexpectedly, a number of them significantly inhibited GABA-stimulated GTPγS binding thus revealing a functional switch with respect to the prototype molecules. Further studies on selected compounds will clarify if they act as negative modulators of the receptor or, instead, as antagonists at the orthosteric binding site.
GABA 受体的正变构调节剂（PAMs）是一种很有前途的替代物，例如巴氯芬，因为它们以更生理的方式作用于受体，因此没有激动剂通常产生的副作用。基于我们对鉴定新的 GABA 受体 PAMs 的兴趣，我们采用了一种合并的方法，从选定的活性化合物（如 GS39783、rac-BHFF 和 BHF177）出发设计新的化学型，最终合成了四类不同的化合物。新化合物单独或在 10 µM GABA 存在下使用 [S]GTPγS 结合测定法进行测试，以评估它们在受体上的功能。出乎意料的是，其中一些化合物显著抑制了 GABA 刺激的 GTPγS 结合，从而显示出相对于原型分子的功能转换。对选定化合物的进一步研究将阐明它们是否作为受体的负变构调节剂起作用，或者作为变构结合位点的拮抗剂起作用。
