Dizocilpine

Dizocilpine (MK-801) is the prototypical high-affinity, selective, non-competitive antagonist of the NMDA glutamate receptor. It is an open-channel blocker: it can only enter and bind once glutamate and glycine have opened the receptor's ion channel, then lodges deep inside the pore at the PCP / MK-801 site, physically occluding the flow of Na⁺ and Ca²⁺ in a use- and voltage-dependent way. Because it becomes trapped behind the closing channel gate, its block is exceptionally long-lasting ('high-trapping' pharmacology): the reason its tritiated (+)-enantiomer, [³H]-(+)-MK-801, is the standard radioligand for labelling the NMDA channel. Its affinity for the channel site is very high: in the [³H]-(+)-MK-801 rat-forebrain homogenate assay the equilibrium dissociation constant (Kd) is ≈1.7 nM, roughly an order of magnitude tighter than PCP or ketamine, and it is strongly selective for the NMDA receptor over other targets. Interrupting NMDA-receptor signalling across cortical, hippocampal and thalamic circuits produces the dissociative state (analgesia, detachment, disordered sensory integration and, at higher exposure, anaesthesia) together with the marked psychotomimetic and amnestic effects that made MK-801 a standard pharmacological model of the positive and cognitive symptoms of schizophrenia. MK-801 was discovered at Merck in the early 1980s and characterised by Wong and colleagues as a potent anticonvulsant and NMDA antagonist. It was pursued as a neuroprotectant for stroke and traumatic brain injury, since blocking NMDA-mediated calcium influx limits excitotoxic cell death. Clinical development was abandoned: non-competitive NMDA antagonists of this class cause dose-dependent psychosis, and dizocilpine produces the reversible neuronal vacuolisation of the posterior cingulate and retrosplenial cortex known as 'Olney's lesions', which appears within about 30 minutes of a modest subcutaneous dose in rodents. It is therefore used essentially only as a laboratory tool, not as a medicine. Dizocilpine is lipophilic and enters the CNS readily. It is cleared by hepatic oxidative metabolism, and its behavioural effects are unusually long-lasting for a dissociative. Detailed human pharmacokinetics are not established because it has never been an approved drug. The dextrorotatory (+)-(5S,10R) enantiomer is the eutomer: the pharmacologically active form used in virtually all research. The (−)-(5R,10S) enantiomer is also an NMDA open-channel blocker but several-fold weaker. The molecule carries two bridgehead stereocentres (C5 and C10), but they are locked in a rigid azabicyclic cage by the 5,10-imine bridge, so only this single enantiomeric pair is geometrically possible. There are no separable diastereomers. (Note: reference sources disagree on the descriptor, the (+)/active form is (5S,10R) per PubChem CID 180081, CAS 77086-21-6 and Sigma-Aldrich/Merck, and some sources including Wikipedia label the enantiomers the opposite way.)