KETOBEMIDONE PLUS (RS)-3-DIMETHYLAMINO-1,1-DIPHENYLBUT-1-ENE (A29) ISMORE POTENT AT NMDA RECEPTORS THAN KETOBEMIDONE ALONE - EVIDENCE FOR A29 AS A NONCOMPETITIVE NMDA RECEPTOR ANTAGONIST

The opioid, ketobemidone, has previously been shown to be a non-compet itive N-methyl-D-aspartate (NMDA) receptor antagonist. In Denmark, ket obemidone is available in a formulation which contains ketobemidone an d a spasmolytic compound, (RS)-3-dimethylamino-1,1-diphenylbut-1-ene, hydrochloride (A29), in a one to five ratio. Using in vitro receptor b inding techniques and an in vitro electrophysiological preparation con sisting of rat cerebral cortex, we have characterized the interaction between A29 and the different glutamate receptor subtypes. A29 selecti vely inhibited binding of the non-competitive NMDA receptor antagonist H-3-MK-801 with a K-i value 16+/-4.5 mu M, but was inactive in assays measuring affinities for other glutamate receptors. In agreement with the binding studies, A29 was found to selectively inhibit responses t o NMDA in the rat cortical wedge preparation, whereas responses to kai nate and AMPA were unaffected. Analysis of dose response curves showed A29 to be a NMDA receptor antagonist with an IC50 value of 100 mu M v ersus responses to 10 mu M NMDA. The inhibitory effects of ketobemidon e and A29 on responses to 10 mu M NMDA were additive. These data show that the combination of A29 and ketobemidone exert more potent antagon ism at the NMDA receptor than does ketobemidone alone.