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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Ketobemidone plus (RS)-3-dimethylamino-1,1-diphenylbut-1-ene (A29) is more potent at NMDA receptors than ketobemidone alone: evidence for A29 as a non-competitive NMDA receptor antagonist.

The opioid, ketobemidone, has previously been shown to be a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. In Denmark, ketobemidone is available in a formulation which contains ketobemidone and a spasmolytic compound, (RS)-3-dimethylamino-1,1-diphenylbut-1-ene, hydrochloride (A29), in a one to five ratio. Using in vitro receptor binding techniques and an in vitro electrophysiological preparation consisting of rat cerebral cortex, we have characterized the interaction between A29 and the different glutamate receptor subtypes. A29 selectively inhibited binding of the non-competitive NMDA receptor antagonist 3H-MK-801 with a Ki value 16 +/- 4.5 microM, but was inactive in assays measuring affinities for other glutamate receptors. In agreement with the binding studies, A29 was found to selectively inhibit responses to NMDA in the rat cortical wedge preparation, whereas responses to kainate and AMPA were unaffected. Analysis of dose response curves showed A29 to be a NMDA receptor antagonist with an IC50 value of 100 microM versus responses to 10 microM NMDA. The inhibitory effects of ketobemidone and A29 on responses to 10 microM NMDA were additive. These data show that the combination of A29 and ketobemidone exert more potent antagonism at the NMDA receptor than does ketobemidone alone.[1]


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