Ibogaine, a hallucinogenic alkaloid claimed to reduce addiction, blocks NMDA receptors in the brain. In cultured rat hippocampal neurons, ibogaine slowly and reversibly blocked NMDA-induced currents with an IC50 of 3.1 µM at −60 mV, while not affecting kainate or GABA currents. The block was use- and voltage-dependent and could be occluded by magnesium. Ibogaine also inhibited dizocilpine binding to NMDA receptors in rat forebrain membranes (IC50, 3.2 µM). In mice, ibogaine fully protected against maximal electroshock seizures (ED50, 31 mg/kg, i.p.) and partially protected against NMDA-induced lethality, confirming in vivo NMDA receptor blockade.
In rats trained to recognize the drug dizocilpine, various NMDA receptor antagonists were tested for their ability to produce similar effects. The dissociative anesthetics dizocilpine, phencyclidine, and ketamine fully substituted for dizocilpine without slowing response rates. Dexoxadrol also fully substituted but reduced response rates by 35%. Memantine, a low-affinity antagonist, fully substituted but only at doses that reduced response rates by 68%. Other low-affinity antagonists showed partial or no substitution, often at rate-reducing doses. The findings indicate that low-affinity NMDA antagonists produce discriminative stimulus effects distinct from those of dissociative anesthetics, with only the more potent low-affinity drugs showing substantial substitution, and then only at doses that impair behavior.
The novel compound RTI-4793-14 binds selectively and with high affinity to a brain site (PCP site 2) that is insensitive to MK-801 and may be associated with biogenic amine transporters. In contrast, MK-801 binds with high affinity only to PCP site 1 (associated with NMDA receptors) and potently blocks NMDA responses, while PCP binds with high affinity to both sites and is moderately potent across several transporter-related measures. RTI-4793-14 is the first selective, high-affinity ligand for PCP site 2.