Kang Heather, Park Pojeong, Bortolotto Zuner A, Brandt Simon D, Colestock Tristan, Wallach Jason, Collingridge Graham L, Lodge David
Centre for Synaptic Plasticity, School of Clinical Sciences, Dorothy Hodgkin Building, University of Bristol, Bristol, BS1 3NY, UK.
Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, Dorothy Hodgkin Building, University of Bristol, Bristol, BS1 3NY, UK.
Neuropharmacology. 2017 Jan;112(Pt A):144-149. doi: 10.1016/j.neuropharm.2016.08.004. Epub 2016 Aug 9.
To avoid legislation based on chemical structure, research chemicals, frequently used for recreational purposes, are continually being synthesized. N-Ethyl-1,2-diphenylethanamine (ephenidine) is a diarylethylamine that has recently become popular with recreational users searching for dissociative hallucinogenic effects. In the present study, the pharmacological basis of its neural actions has been investigated, initially by assessing its profile in central nervous system receptor binding assays and subsequently in targeted electrophysiological studies. Ephenidine was a potent inhibitor of H-MK-801 binding (Ki: 66 nM), implying that it acts at the PCP site of the N-methyl-d-aspartate (NMDA) receptor. It also showed modest activity at dopamine (379 nM) and noradrenaline (841 nM) transporters and at sigma 1 (629 nM) and sigma 2 (722 nM) binding sites. In experiments of extracellular recording of field excitatory postsynaptic potentials (fEPSPs) from area CA1 of rat hippocampal slices, ephenidine, 1 and 10 μM, respectively, produced a 25% and a near maximal inhibition of the NMDA receptor mediated fEPSP after 4 h superfusion. By contrast, ephenidine (50 μM) did not affect the AMPA receptor mediated fEPSPs. In whole cell patch clamp recordings, from hippocampal pyramidal cells, ephenidine (10 μM) blocked NMDA receptor-mediated EPSCs in a highly voltage-dependent manner. Additionally, ephenidine, 10 μM, blocked the induction of long term potentiation (LTP) in CA1 induced by theta burst stimulation. The present data show that the new psychoactive substance, ephenidine, is a selective NMDA receptor antagonist with a voltage-dependent profile similar to ketamine. Such properties help explain the dissociative, cognitive and hallucinogenic effects in man. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'.
为避免基于化学结构的立法，常用于娱乐目的的研究化学品不断被合成。N-乙基-1,2-二苯基乙胺（依非尼丁）是一种二芳基乙胺，最近在寻求解离性致幻效果的娱乐使用者中变得流行起来。在本研究中，对其神经作用的药理学基础进行了研究，首先通过评估其在中枢神经系统受体结合试验中的特征，随后进行靶向电生理研究。依非尼丁是H-MK-801结合的强效抑制剂（Ki：66 nM），这意味着它作用于N-甲基-D-天冬氨酸（NMDA）受体的苯环己哌啶位点。它在多巴胺（379 nM）和去甲肾上腺素（841 nM）转运体以及σ1（629 nM）和σ2（722 nM）结合位点也表现出适度活性。在大鼠海马切片CA1区场兴奋性突触后电位（fEPSP）的细胞外记录实验中，1 μM和10 μM的依非尼丁在4小时灌流后分别对NMDA受体介导的fEPSP产生25%和接近最大程度的抑制。相比之下，50 μM的依非尼丁不影响AMPA受体介导的fEPSP。在海马锥体细胞的全细胞膜片钳记录中，10 μM的依非尼丁以高度电压依赖性方式阻断NMDA受体介导的兴奋性突触后电流（EPSC）。此外，10 μM的依非尼丁阻断了θ波爆发刺激诱导的CA1区长时程增强（LTP）。目前的数据表明，新型精神活性物质依非尼丁是一种选择性NMDA受体拮抗剂，其电压依赖性特征与氯胺酮相似。这些特性有助于解释其在人体中的解离、认知和致幻作用。本文是名为“离子型谷氨酸受体”的特刊的一部分。
