Orphenadrine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist: binding and patch clamp studies

Summary Orphenadrine has been used as an antiparkinsonian, antispastic and analgesic drug for many years. Here we show that orphenadrine inhibits ³H]MK-801 binding to the phencyclidine (PCP) binding site of the N-methyl-D-aspartate (NMDA)-receptor in homogenates of postmortem human frontal cortex with a K_i-value of 6.0 ± 0.7 M. The NMDA receptor antagonistic effects of orphenadrine were assessed using concentration- and patch-clamp techniques on cultured superior colliculus neurones. Orphenadrine blocked open NMDA receptor channels with fast kinetics and in a strongly voltage-dependent manner. The IC₅₀-value against steady state currents at –70mV was 16.2 ± 1.6 M (n=6). Orphenadrine exhibited relatively fast, concentration-dependent open channel blocking kinetics (K_on 0.013 ± 0.002 10⁶M^–1S^–1) whereas the offset rate was concentration-independent (K_off 0.230 ± 0.004 S^–1). Calculation of the ratio K_off/K_on revealed an apparent K_d-value of 17.2 M which is nearly identical to the IC₅₀ calculated at equilibrium.