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.
Kornhuber
J
J
Department of Psychiatry, University of Würzburg, Germany.
Parsons
C G
CG
Hartmann
S
S
Retz
W
W
Kamolz
S
S
Thome
J
J
Riederer
P
P
D000368:Aged; D001667:Binding, Competitive / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000378:metabolism / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009966:Orphenadrine / Q000378:metabolism / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017478:Receptors, Phencyclidine / Q000187:drug effects / Q000378:metabolism; D013477:Superior Colliculi / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; D018727:Muscarinic Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D017478:Receptors, Phencyclidine; D016291:Dizocilpine Maleate; D009966:Orphenadrine