Diphenidine

Diphenidine is a diarylethylamine dissociative and an antagonist of the NMDA glutamate receptor. Like ketamine and PCP it is an open-channel blocker: it enters the receptor's ion channel once glutamate has opened it and binds within the pore (the PCP / dizocilpine site), physically blocking cation flux in a use- and voltage-dependent way. Electrophysiology shows it lowers NMDA-mediated currents to a degree similar to ketamine, but with a slower onset. By interrupting NMDA signalling in cortical and thalamic circuits it produces the dissociative state: analgesia, a sense of detachment from body and environment, disordered sensory integration and, at high doses, anaesthesia with reported 'bizarre somatosensory phenomena' and transient anterograde amnesia. Its two enantiomers differ markedly: the (S)-enantiomer is roughly 40 times more potent than the (R) at the NMDA receptor. NMDA-channel block dominates its activity: in a receptor-binding panel diphenidine's tightest affinity is for the NMDA receptor (Ki ≈ 18 nM: more potent than ketamine or PCP). It is not wholly selective, also binding with submicromolar affinity to the σ2 (≈193 nM), σ1 (≈290 nM) receptors and the dopamine transporter (≈317 nM), plus weaker antihistamine (H1/H3, ~1 µM) and muscarinic activity. These may contribute to its stimulating, psychotomimetic character. It is only a weak functional monoamine-reuptake inhibitor (DAT IC50 ≈ 2 µM). It is extensively metabolised in the liver (phase-I hydroxylation of the piperidine and aromatic rings, then conjugation). Human pharmacokinetics are poorly defined because it exists only as an unapproved research chemical, and its effects are reported to be unusually long-lasting for a dissociative.