Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 14220 Prague 4, Czech Republic; Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 14220 Prague 4, Czech Republic.
Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.
Biochem Pharmacol. 2021 Apr;186:114460. doi: 10.1016/j.bcp.2021.114460. Epub 2021 Feb 8.
N-methyl-D-aspartaterecepro receptor (NMDARs) are a subclass of glutamate receptors, which play an essential role in excitatory neurotransmission, but their excessive overactivation by glutamate leads to excitotoxicity. NMDARs are hence a valid pharmacological target for the treatment of neurodegenerative disorders; however, novel drugs targeting NMDARs are often associated with specific psychotic side effects and abuse potential. Motivated by currently available treatment against neurodegenerative diseases involving the inhibitors of acetylcholinesterase (AChE) and NMDARs, administered also in combination, we developed a dually-acting compound 7-phenoxytacrine (7-PhO-THA) and evaluated its neuropsychopharmacological and drug-like properties for potential therapeutic use. Indeed, we have confirmed the dual potency of 7-PhO-THA, i.e. potent and balanced inhibition of both AChE and NMDARs. We discovered that it selectively inhibits the GluN1/GluN2B subtype of NMDARs via an ifenprodil-binding site, in addition to its voltage-dependent inhibitory effect at both GluN1/GluN2A and GluN1/GluN2B subtypes of NMDARs. Furthermore, whereas NMDA-induced lesion of the dorsal hippocampus confirmed potent anti-excitotoxic and neuroprotective efficacy, behavioral observations showed also a cholinergic component manifesting mainly in decreased hyperlocomotion. From the point of view of behavioral side effects, 7-PhO-THA managed to avoid these, notably those analogous to symptoms of schizophrenia. Thus, CNS availability and the overall behavioral profile are promising for subsequent investigation of therapeutic use.
N-甲基-D-天冬氨酸受体（NMDARs）是谷氨酸受体的一个亚类，在兴奋性神经递质传递中发挥着重要作用，但谷氨酸的过度过度激活会导致兴奋性毒性。因此，NMDAR 是治疗神经退行性疾病的有效药物靶点；然而，靶向 NMDAR 的新型药物通常与特定的精神病副作用和滥用潜力有关。受目前针对涉及乙酰胆碱酯酶（AChE）和 NMDAR 抑制剂的神经退行性疾病的治疗方法的启发，我们还联合使用了这些抑制剂，我们开发了一种双重作用化合物 7-苯氧基他克林（7-PhO-THA），并评估了其神经精神药理学和类药性，以确定其潜在的治疗用途。事实上，我们已经证实了 7-PhO-THA 的双重效力，即对 AChE 和 NMDAR 都具有强大而平衡的抑制作用。我们发现，它通过ifenprodil 结合位点选择性抑制 NMDAR 的 GluN1/GluN2B 亚型，此外，它还对 GluN1/GluN2A 和 GluN1/GluN2B 亚型的 NMDAR 具有电压依赖性抑制作用。此外，NMDA 诱导的背海马损伤证实了其强大的抗兴奋毒性和神经保护作用，行为观察也表明存在主要表现为运动过度减少的胆碱能成分。从行为副作用的角度来看，7-PhO-THA 设法避免了这些副作用，特别是那些类似于精神分裂症症状的副作用。因此，中枢神经系统的可用性和整体行为特征为进一步研究治疗用途提供了希望。
