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

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 Ki-value of 6.0 +/- 0.7 microM. 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 -70 mV was 16.2 +/- 1.6 microM (n = 6). Orphenadrine exhibited relatively fast, concentration-dependent open channel blocking kinetics (Kon 0.013 +/- 0.002 10(6) M-1S-1) whereas the offset rate was concentration-independent (Koff 0.230 +/- 0.004 S-1). Calculation of the ratio Koff/Kon revealed an apparent Kd-value of 17.2 microM which is nearly identical to the IC50 calculated at equilibrium.