Budipine is a low affinity, N-methyl-D-aspartate receptor antagonist: patch clamp studies in cultured striatal, hippocampal, cortical and superior colliculus neurones.
The NMDA receptor antagonistic effects of budipine were assessed using concentration- and patch-clamp techniques on cultured striatal, hippocampal, cortical and superior colliculus neurones. Inward current responses of striatal neurones to NMDA (200 microM) at -70 mV were antagonized by budipine in a concentration-dependent manner (50% inhibitory concentration (IC50) 59.4 +/- 10.7 microM, n = 17) with 24 times lower potency than memantine but similar potency to amantadine. In striatal neurones, budipine blocked outward currents at +70 mV with an IC50 of 827 microM, suggesting that the binding site is less deep in the channel (delta = 0.45) than for memantine. However, more detailed analysis of the fractional block by budipine 300 microM in hippocampal neurones gave a delta-value of 0.90, but revealed that 28% block is mediated at a voltage-independent site. This voltage-insensitive site was accessible in the absence of agonist. Budipine exhibited concentration-dependent open channel blocking kinetics (kappa(on) = 0.71 x 10(4) M(-1) s(-1)) whereas the fast offset rate was concentration-independent (kappa(off) = 0.63 s(-1)). Calculation of the ratio kappa(off)/kappa(on) revealed an apparent Kd value of 88.7 microM. Budipine, memantine and amantadine had similar effects against NMDA-induced currents in cultured hippocampal, cortical and superior colliculus neurones, although amantadine was somewhat more potent in cultured striatal neurones. The relevance of NMDA receptor antagonism to the anti-Parkinsonian effects of budipine remains to be established.
Parsons
C G
CG
Department of Pharmacology, Merz and Co., Frankfurt, Germany. chris.parsons@merz.de
Hartmann
S
S
Spielmanns
P
P
D000547:Amantadine / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D004622:Embryo, Mammalian; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D008559:Memantine / Q000494:pharmacology; D017072:Neostriatum / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013477:Superior Colliculi / Q000187:drug effects / Q000502:physiology
D000978:Antiparkinson Agents; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D000547:Amantadine; C026710:budipine; D008559:Memantine