Jensen Anders A, Mosbacher Johannes, Elg Susanne, Lingenhoehl Kurt, Lohmann Tania, Johansen Tommy N, Abrahamsen Bjarke, Mattsson Jan P, Lehmann Anders, Bettler Bernhard, Bräuner-Osborne Hans
NeuroScience PharmaBiotec Research Centre, Department of Medicinal Chemistry, the Royal Danish School of Pharmacy, Copenhagen, Denmark.
Mol Pharmacol. 2002 Jun;61(6):1377-84. doi: 10.1124/mol.61.6.1377.
The actions of the anticonvulsant gabapentin [1-(aminomethyl)cyclohexaneacetic acid, Neurontin] have been somewhat enigmatic until recently, when it was claimed to be a gamma-aminobutyric acid-B (GABA(B)) receptor agonist acting exclusively at a heterodimeric complex containing the GABA(B(1a)) splice variant (Mol Pharmacol 2001;59:144-152). In this study, we have investigated the effects of gabapentin on recombinant GABA(B(1a)) and GABA(B(1b)) receptors coexpressed with GABA(B(2)) in five different functional recombinant assays, its ability to inhibit [(3)H]GABA binding in a GABA(B) receptor-selective binding assay using rat synaptic membranes, and its ability to inhibit transient lower esophageal sphincter relaxations in Labrador retriever dogs. Up to a concentration of 1 mM, gabapentin displayed no agonistic effects on either the GABA(B(1a,2)) or the GABA(B(1b,2)) heterodimer, when these were expressed in Xenopus laevis oocytes or mammalian cells and assayed by means of electrophysiology, calcium mobilization, inositol phosphate, and fluorometry assays. Gabapentin did not displace [(3)H]GABA from GABA(B) receptor sites in rat synaptic membranes. Finally, in contrast to the classic GABA(B) receptor agonist baclofen, gabapentin was unable to inhibit transient lower esophageal sphincter relaxations in dogs. Because of high levels of GABA(B(1a)) in the canine nodose ganglion, this finding indirectly supports the inactivity of gabapentin on the GABA(B(1a,2)) heterodimer demonstrated in various in vitro assays. In light of these results, we find it highly questionable that gabapentin is a GABA(B) receptor agonist. Hence, the anticonvulsive effects of the compound have to arise from GABA(B) receptor-independent mechanisms. This also implies that the first GABA(B) receptor splice variant-selective ligand remains to be discovered.
抗惊厥药加巴喷丁[1-(氨甲基)环己烷乙酸，Neurontin]的作用一直有些神秘，直到最近，有研究称它是一种γ-氨基丁酸B（GABA(B)）受体激动剂，专门作用于含有GABA(B(1a))剪接变体的异二聚体复合物（《分子药理学》2001年；59:144 - 152）。在本研究中，我们在五种不同的功能性重组试验中研究了加巴喷丁对与GABA(B(2))共表达的重组GABA(B(1a))和GABA(B(1b))受体的影响，它在使用大鼠突触膜的GABA(B)受体选择性结合试验中抑制[(3)H]GABA结合的能力，以及它在拉布拉多猎犬中抑制食管下括约肌短暂松弛的能力。在爪蟾卵母细胞或哺乳动物细胞中表达并通过电生理学、钙动员、肌醇磷酸和荧光测定法检测时，加巴喷丁在高达1 mM的浓度下，对GABA(B(1a,2))或GABA(B(1b,2))异二聚体均无激动作用。加巴喷丁不能从大鼠突触膜的GABA(B)受体位点上取代[(3)H]GABA。最后，与经典的GABA(B)受体激动剂巴氯芬相反，加巴喷丁不能抑制犬的食管下括约肌短暂松弛。由于犬的结状神经节中GABA(B(1a))水平较高，这一发现间接支持了加巴喷丁在各种体外试验中对GABA(B(1a,2))异二聚体无活性的结论。鉴于这些结果，我们认为加巴喷丁是否为GABA(B)受体激动剂非常值得怀疑。因此，该化合物的抗惊厥作用必定源于不依赖GABA(B)受体的机制。这也意味着首个GABA(B)受体剪接变体选择性配体仍有待发现。
