THE ANTIPARKINSONIAN DRUGS BUDIPINE AND BIPERIDEN ARE USE-DEPENDENT (UNCOMPETITIVE) NMDA RECEPTOR ANTAGONISTS

N-Methyl-D-aspartate- (NMDA-) evoked [H-3]acetylcholine release in rabbit caudate nucleus slices was inhibited by the antiparkinsonian drugs budipine (1-tert-butyl-4,4-diphenylpiperidine) and biperiden (1-bicyclo[2.2.1.]hept-5-en-2-yl-1-phenyl-3-piperidino propanol) yielding functional K-i values of 4.6 and 8.8 mu M. In contrast to the competitive antagonist 2-amino-5-phosphonopentaonate, budipine and biperidene significantly reduced both the apparent K-D and the E(max) value of NMDA. Moreover, they displaced [H-3]MK-801 specifically bound to membranes of the same tissue, although with low affinity (IC50: 38 and 92 mu M). It is concluded that budipine and biperiden are use-dependent (uncompetitive) antagonists at the NMDA receptor, binding to the receptor-linked ion channel, but probably not to the MK-801 binding site. NMDA antagonism may contribute to the antiparkinsonian effects of budipine.