Pharmacological properties of trimebutine and N-monodesmethyltrimebutine.
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 microM) and nor-TMB (Ki = 0.73 +/- 0.02 microM) displaced [3H]batrachotoxin from its binding site with affinities similar to that of bupivacaine (Ki = 7.1 +/- 0.9 microM). nor-TMB was found to block veratridine-induced glutamate release with an IC50 value of 8.5 microM, which is very similar to that of bupivacaine (IC50 = 8.2 microM); the effect of TMB was limited to 50% inhibition at 100 microM. 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 microM, 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 microM) 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.
Roman
F J
FJ
Institut de Recherche Jouveinal/Parke Davis, Fresnes Cedex, France. francois.roman@wl.com
Lanet
S
S
Hamon
J
J
Brunelle
G
G
Maurin
A
A
Champeroux
P
P
Richard
S
S
Alessandri
N
N
Gola
M
M
D000818:Animals; D001496:Batrachotoxins / Q000378:metabolism; D001667:Binding, Competitive; D002460:Cell Line; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism*; D003315:Cornea / Q000502:physiology; D004622:Embryo, Mammalian; D004625:Embryo, Nonmammalian; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000502:physiology*; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000378:metabolism; D051662:Kv1.1 Potassium Channel; D051663:Kv1.2 Potassium Channel; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology*; D013237:Stereoisomerism; D013574:Synaptosomes / Q000378:metabolism*; D014287:Trimebutine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014982:Xenopus laevis
D001496:Batrachotoxins; C496946:KCNA1 protein, human; C496969:KCNA2 protein, human; C496972:Kcna2 protein, rat; D051663:Kv1.2 Potassium Channel; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D051662:Kv1.1 Potassium Channel; D018698:Glutamic Acid; C053065:N-desmethyltrimebutine; D008012:Lidocaine; D014287:Trimebutine