Ephenidine: A new psychoactive agent with ketamine-like NMDA receptor antagonist properties
Heather Kang, Pojeong Park, Zuner A. Bortolotto, Simon D. Brandt, Tristan Colestock, Jason Wallach, Graham L. Collingridge, David Lodge
Neuropharmacology August 10, 2016 DOI: 10.1016/j.neuropharm.2016.08.004 via OpenAlex
Summary
Ephenidine, a new psychoactive substance, acts as a selective NMDA receptor antagonist by binding to the PCP site (Ki: 66 nM). It also shows modest activity at dopamine and noradrenaline transporters and at sigma 1 and sigma 2 binding sites. In rat hippocampal slices, ephenidine (1 and 10 μM) inhibited NMDA receptor-mediated field excitatory postsynaptic potentials by 25% and near maximally after 4 hours, without affecting AMPA receptor-mediated responses. It blocked NMDA receptor-mediated EPSCs in a voltage-dependent manner and prevented the induction of long-term potentiation. These properties resemble ketamine and help explain its dissociative, cognitive, and hallucinogenic effects in humans.
Study at a glance
| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Rat hippocampal slices |
| Intervention | Ephenidine |
| Dose | 1 μM, 10 μM, 50 μM |
| Duration | 4-hour superfusion |
| Keywords | Nmda receptor Long-term potentiation Ampa receptor Excitatory postsynaptic potential Pharmacology |
| Citations | 29 |
| Key finding | Ephenidine is a selective NMDA receptor antagonist with a voltage-dependent profile similar to ketamine, blocking NMDA receptor-mediated synaptic transmission and long-term potentiation. |
Abstract
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'.