Regional variations in the pharmacology of NMDA receptor channel blockers: implications for therapeutic potential.

Quantitative receptor autoradiography was used to examine the regional binding characteristics of a diverse group of N-methyl-D-aspartate (NMDA)-receptor channel blockers that varied in potency 10(5)-fold. Full competition curves were generated in each of six brain regions for 11 different compounds. MK-801 was the most potent compound studied, with an IC50 of approximately 10 nM in the forebrain regions and 24 nM in the cerebellar granule cell layer (p < 0.05). The binding affinities of nine of the 11 compounds examined were significantly different in cerebellar granule cell layer than in forebrain regions. In addition, the apparent Hill slopes of five of the compounds were significantly different in cerebellum compared with forebrain. That the rank order of drug potencies in cerebellar diverges from that in forebrain suggests that cerebellar NMDA-receptor ion channels differ pharmacologically from those in forebrain. There was a general trend that drugs known to be well tolerated in humans (remacemide hydrochloride and its metabolites, amantadine, budipine, and memantine) had lower affinities than compounds with severe neurobehavioral or psychotomimetic effects. Moreover, all of the compounds known to be well tolerated in humans had a significantly higher affinity in the cerebellum than in forebrain regions, in contrast to MK-801, 1-[1-(2-thienyl)cyclohexyl]-piperidine hydrochloride (TCP), phencyclidine (PCP), and ketamine, which had lower affinities in cerebellum. Our results are consistent with the notion that low affinity (rapid kinetics) and, possibly, subunit specificity (as indicated by distinct regional pharmacologies) may be important determinants of the clinical tolerability of NMDA-receptor channel blockers.