title: Ephenidine: A new psychoactive agent with ketamine-like NMDA receptor antagonist properties.
abstract: 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 of3H-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'.
authors: Centre for Synaptic Plasticity, School of Clinical Sciences, Dorothy Hodgkin Building, University of Bristol, Bristol, BS1 3NY, UK.
authors: Heather
authors: H
authors: Kang
authors: Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, Dorothy Hodgkin Building, University of Bristol, Bristol, BS1 3NY, UK.
authors: Pojeong
authors: P
authors: Park
authors: Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, Dorothy Hodgkin Building, University of Bristol, Bristol, BS1 3NY, UK.
authors: Zuner A
authors: ZA
authors: Bortolotto
authors: School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, UK.
authors: Simon D
authors: SD
authors: Brandt
authors: Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, PA, USA.
authors: Tristan
authors: T
authors: Colestock
authors: Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, PA, USA.
authors: Jason
authors: J
authors: Wallach
authors: Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, Dorothy Hodgkin Building, University of Bristol, Bristol, BS1 3NY, UK; Department of Physiology, University of Toronto, Toronto, ON, M5S1A8, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada.
authors: Graham L
authors: GL
authors: Collingridge
authors: Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, Dorothy Hodgkin Building, University of Bristol, Bristol, BS1 3NY, UK. Electronic address: David.Lodge@Bristol.ac.uk.
authors: David
authors: D
authors: Lodge
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000493:pharmacokinetics; D004983:Ethanolamines / Q000493:pharmacokinetics / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D007649:Ketamine / Q000493:pharmacokinetics / Q000494:pharmacology*; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D010627:Phenethylamines / Q000494:pharmacology*; D011619:Psychotropic Drugs / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000378:metabolism / Q000502:physiology*
chemical_list: D004983:Ethanolamines; D018691:Excitatory Amino Acid Antagonists; C120417:N-ethyl-1,2-diphenylethanolamine; D010627:Phenethylamines; D011619:Psychotropic Drugs; D016194:Receptors, N-Methyl-D-Aspartate; C000621156:ephenidine; D007649:Ketamine; D016291:Dizocilpine Maleate
keywords: Dissociative hallucinogen; Ephenidine; Ketamine; Legal high; Long-term potentiation; MK-801 binding; NMDA receptor; Outward rectification