1,2-Diarylethylamines such as diphenidine (DPH) and 2-methoxy-diphenidine (2-MXP) are sold as 'legal highs' and have been linked to fatal and non-fatal overdoses. Binding studies at 46 central nervous system receptors show these compounds are relatively selective N-methyl-D-aspartate receptor (NMDAR) antagonists with weak off-target inhibition of dopamine and norepinephrine reuptake. In rats, DPH and 2-MXP significantly reduced prepulse inhibition of startle (PPI), an effect seen with dissociative drugs like phencyclidine (PCP) and ketamine. DPH acted with a median effective dose (ED50) of 9.5 mg/kg, less potent than PCP and ketamine.
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.