Pharmacological properties of trimebutine and N-monodesmethyltrimebutine

Trimebutine [2-dimethylamino-2-phenylbutyl-3,4,5-trimethoxy-benzoate hydrog en maleate (TMB)] has been demonstrated to be active for relieving abdomina l pain in humans. To better understand its mechanism of action, we have tes ted TMB; nor-TMB, its main metabolite in humans; and their respective stere oisomers for their affinity toward sodium channels labeled by [H-3]batracho toxin, their effect on sodium, potassium, and calcium currents in rat dorsa l root ganglia neurons, and their effect on veratridine-induced glutamate r elease from rat spinal cord slices. TMB has also been tested in an animal m odel of local anesthesia, TMB (K-i = 2.66 +/- 0.15 mu M) and nor-TMB (K-i = 0.73 +/- 0.02 mu M) displaced [H-3]batrachotoxin from its binding site wit h affinities similar to that of bupivacaine (K-i = 7.1 +/- 0.9 mu M), nor-T MB was found to block veratridine-induced glutamate release with an IC50 va lue of 8.5 mu M, which is very similar to that of bupivacaine (IC50 = 8.2 m u M); the effect of TMB was limited to 50% inhibition at 100 mu M. TMB and nor-TMB blocked sodium currents in sensory neurons from rat dorsal root gan glia (IC50 = 0.83 +/- 0.09 and 1.23 +/- 0.19 mu M, respectively), whereas n o effect was observed on calcium currents at the same concentrations. A lim ited effect was observed on potassium currents (IC50 = 23 +/- 6 at 10 mu M) for TMB, In vivo, when tested in the rabbit corneal reflex, TMB displayed a local anesthetic activity 17-fold more potent than that of lidocaine.