Scott Peter J H, Shao Xia, Desmond Timothy J, Hockley Brian G, Sherman Phillip, Quesada Carole A, Frey Kirk A, Koeppe Robert A, Kilbourn Michael R, Bohnen Nicolaas I
Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, United States; The Interdepartmental Program in Medicinal Chemistry, The University of Michigan, Ann Arbor, Michigan 48109, United States.
Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
ACS Med Chem Lett. 2016 Jun 1;7(8):746-50. doi: 10.1021/acsmedchemlett.5b00435. eCollection 2016 Aug 11.
Clarithromycin is a potential treatment for hypersomnia acting through proposed negative allosteric modulation of GABAA receptors. We were interested whether this therapeutic benefit might extend to Parkinson's disease (PD) patients because GABAergic neurotransmission is implicated in postural control. Prior to initiating clinical studies in PD patients, we wished to better understand clarithromycin's mechanism of action. In this work we investigated whether the proposed activity of clarithromycin at the GABAA receptor is associated with the benzodiazepine binding site using in vivo [(11)C]flumazenil positron emission tomography (PET) in primates and ex vivo [(3)H]flumazenil autoradiography in rat brain. While the studies demonstrate that clarithromycin does not change the K d of FMZ, nor does it competitively displace FMZ, there is preliminary evidence from the primate PET imaging studies that clarithromycin delays dissociation and washout of flumazenil from the primate brain in a dose-dependent fashion. These findings would be consistent with the proposed GABAA allosteric modulator function of clarithromycin. While the results are only preliminary, further investigation of the interaction of clarithromycin with GABA receptors and/or GABAergic medications is warranted, and therapeutic applications of clarithromycin alone or in combination with flumazenil, to treat hyper-GABAergic status in PD at minimally effective doses, should also be pursued.
克拉霉素是一种通过对GABAA受体进行负性变构调节来治疗发作性睡病的潜在药物。我们感兴趣的是，这种治疗益处是否可能扩展到帕金森病（PD）患者，因为GABA能神经传递与姿势控制有关。在对PD患者开展临床研究之前，我们希望更好地了解克拉霉素的作用机制。在这项研究中，我们使用灵长类动物体内[(11)C]氟马西尼正电子发射断层扫描（PET）和大鼠脑体外[(3)H]氟马西尼放射自显影技术，研究了克拉霉素在GABAA受体上的假定活性是否与苯二氮䓬结合位点相关。虽然研究表明克拉霉素不会改变氟马西尼的解离常数（Kd），也不会竞争性取代氟马西尼，但灵长类动物PET成像研究有初步证据表明，克拉霉素能以剂量依赖的方式延迟氟马西尼从灵长类动物脑中的解离和清除。这些发现与克拉霉素作为GABAA变构调节剂的假定功能一致。虽然结果只是初步的，但仍有必要进一步研究克拉霉素与GABA受体和/或GABA能药物的相互作用，同时也应探索单独使用克拉霉素或与氟马西尼联合使用，以最低有效剂量治疗PD患者高GABA能状态的治疗应用。
