Abstract
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 (Ki = 2.66 ± 0.15 μM) and nor-TMB (Ki = 0.73 ± 0.02 μM) displaced [3H]batrachotoxin from its binding site with affinities similar to that of bupivacaine (Ki = 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.
Footnotes
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Send reprint requests to: Dr. François J. Roman, Institut de Recherche Jouveinal/Parke-Davis, 11-13, rue de la Loge, BP 100, 94263 Fresnes Cedex, France. E-mail: francois.roman{at}wl.com
- Abbreviations:
- NMDA
- N-methyl-d-aspartate
- IBS
- irritable bowel syndrome
- TMB
- trimebutine
- Received September 23, 1998.
- Accepted February 1, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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