Vol. 289, Issue 3, 1391-1397, June 1999

Pharmacological Properties of Trimebutine and N-Monodesmethyltrimebutine

Francois J. Roman, Sandrine Lanet, Jacques Hamon, Gilles Brunelle, Anne Maurin, Pascal Champeroux, Serge Richard, Nicole Alessandri and Maurice Gola

Institut de Recherche Jouveinal/Parke Davis, Fresnes Cedex, France (F.J.R., S.L., J.H., G.B.); Centre de Recherches Biologiques, Chemin de Montifault, Baugy, France (A.M., P.C., S.R.); and Laboratoire de Neurobiologie, Unité Propre de Recherche, Centre National de la Recherche Scientifique, Marseille Cedex, France (N.A., M.G.)

Trimebutine [2-dimethylamino-2-phenylbutyl-3,4,5-trimethoxybenzoate hydrogen maleate (TMB)] has been demonstrated to be active for relieving abdominal pain in humans. To better understand its mechanism of action, we have tested TMB; nor-TMB, its main metabolite in humans; and their respective stereoisomers for their affinity toward sodium channels labeled by [³H]batrachotoxin, their effect on sodium, potassium, and calcium currents in rat dorsal root ganglia neurons, and their effect on veratridine-induced glutamate release from rat spinal cord slices. TMB has also been tested in an animal model of local anesthesia. TMB (K_i = 2.66 ± 0.15 µM) and nor-TMB (K_i = 0.73 ± 0.02 µM) displaced [³H]batrachotoxin from its binding site with affinities similar to that of bupivacaine (K_i = 7.1 ± 0.9 µM). nor-TMB was found to block veratridine-induced glutamate release with an IC₅₀ value of 8.5 µM, which is very similar to that of bupivacaine (IC₅₀ = 8.2 µM); the effect of TMB was limited to 50% inhibition at 100 µM. TMB and nor-TMB blocked sodium currents in sensory neurons from rat dorsal root ganglia (IC₅₀ = 0.83 ± 0.09 and 1.23 ± 0.19 µM, respectively), whereas no effect was observed on calcium currents at the same concentrations. A limited effect was observed on potassium currents (IC₅₀ = 23 ± 6 at 10 µM) 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.