Target Validation Information
TTD ID T29303
Target Name Sodium channel unspecific (NaC)
Type of Target
Successful
Drug Potency against Target Benzocaine Drug Info IC50 = 258000 nM [9]
Bupivacaine Drug Info IC50 = 6800 nM [10]
Levobupivacaine Drug Info IC50 = 10000 nM [11]
Mepivacaine Drug Info IC50 = 149000 nM [18]
Oxybuprocaine Drug Info IC50 = 6310 nM [16]
Permethrin Drug Info IC50 = 50000 nM [8]
Phenytoin Drug Info IC50 = 58000 nM [17]
Ropivacaine Drug Info IC50 = 20600 nM [10]
Zonisamide Drug Info Ki = 1 nM [13]
Carisbamate Drug Info IC50 = 69000 nM [14]
Ralfinamide Drug Info IC50 = 10000 nM [12]
Drug Info IC50 = 5500 nM [4]
2-(1-Pentyl-hexyl)-4-phenyl-1H-imidazole Drug Info IC50 = 86 nM [6]
2-Hexyl-4-(4-isobutyl-phenyl)-1H-imidazole Drug Info IC50 = 28 nM [6]
2-Hydroxy-2-phenyl-nonanoic acid amide Drug Info IC50 = 9000 nM [1]
4-Biphenyl-4-yl-2-(1-pentyl-hexyl)-1H-imidazole Drug Info IC50 = 8 nM [6]
4-Biphenyl-4-yl-2-(1-propyl-butyl)-1H-imidazole Drug Info IC50 = 100 nM [6]
4-Biphenyl-4-yl-2-cyclohexylmethyl-1H-imidazole Drug Info IC50 = 70 nM [6]
4-Biphenyl-4-yl-2-hexyl-1H-imidazole Drug Info IC50 = 16 nM [6]
4-Biphenyl-4-yl-2-methyl-1H-imidazole Drug Info IC50 = 1460 nM [6]
5-Heptyl-5-phenyl-imidazolidine-2,4-dione Drug Info IC50 = 5000 nM [1]
5-Hexyl-5-phenyl-imidazolidine-2,4-dione Drug Info IC50 = 13000 nM [1]
5-Nonyl-5-phenyl-imidazolidine-2,4-dione Drug Info IC50 = 5000 nM [1]
L-741742 Drug Info Ki = 1900 nM [2]
LIDOFLAZINE Drug Info Ki = 77 nM [7]
LOMERIZINE Drug Info IC50 = 26 nM [4]
LUBELUZOLE Drug Info IC50 = 280 nM [4]
NS-7 Drug Info IC50 = 1000 nM [4]
PD-85639 Drug Info Ki = 260 nM [7]
PD-85639 Drug Info IC50 = 46 nM [4]
SIPATRIGINE Drug Info IC50 = 17850 nM [5]
SIPATRIGINE Drug Info IC50 = 5300 nM [4]
U-92032 Drug Info IC50 = 360 nM [3]
Action against Disease Model Phenytoin Drug Info The results obtained by Huntingdon Research Centre participating in a blind trial of the micromass assay for the prediction of teratogenic potential are presented. Twenty-five coded compounds were tested without S-9 mix using a pre-agreed protocol; three compounds were later tested with S-9. The data were assessed for sensitivity, specificity and accuracy using three separate sets of criteria based on either concentration (the <500 m ug/ml rule (i) and the <50 m ug/ml rule (ii)) or specific inhibition of cell differentiation at relatively non-cytotoxic concentrations (the 2-fold rule (iii)). The best in vivo/in vitro correlation was obtained using the 2-fold rule; the <500 m ug/ml rule was the most sensitive but gave a high false positive rate and the <50 m ug/ml rule was of low overall accuracy (60%). It is suggested that selective inhibition of differentiation of one cell type and cytotoxicity at low dose levels may also indicate risk of embryo-foeto toxicity, a factor to be considered with the pharmacokinetics of the compound. The teratogens procarbazine, methotrexate and caffeine were not detected; diphenhydramine and furazolidone initially classified as non-teratogens in vivo, were predicted as teratogens by the micromass assay. [15]
References
REF 1 Comparative molecular field analysis of hydantoin binding to the neuronal voltage-dependent sodium channel. J Med Chem. 1999 May 6;42(9):1537-45.
REF 2 1-(3-Cyanobenzylpiperidin-4-yl)-5-methyl-4-phenyl-1, 3-dihydroimidazol-2-one: a selective high-affinity antagonist for the human dopamine D(4) rece... J Med Chem. 1999 Jul 15;42(14):2706-15.
REF 3 Discovery of (2S)-1-(4-amino-2,3,5- trimethylphenoxy)-3-[4-[4-(4- fluorobenzyl)phenyl]-1-piperazinyl]-2-propanol dimethanesulfonate (SUN N8075): a ... J Med Chem. 2000 Sep 7;43(18):3372-6.
REF 4 Medicinal chemistry of neuronal voltage-gated sodium channel blockers. J Med Chem. 2001 Jan 18;44(2):115-37.
REF 5 Synthesis and structure-activity relationships of 6,7-benzomorphan derivatives as use-dependent sodium channel blockers for the treatment of stroke. J Med Chem. 2002 Aug 15;45(17):3755-64.
REF 6 2-Alkyl-4-arylimidazoles: structurally novel sodium channel modulators. Bioorg Med Chem Lett. 2004 Jul 5;14(13):3521-3.
REF 7 Synthesis and pharmacological evaluation of phenylacetamides as sodium-channel blockers. J Med Chem. 1994 Jan 21;37(2):268-74.
REF 8 WIN 17317-3, a new high-affinity probe for voltage-gated sodium channels. Biochemistry. 1999 Aug 24;38(34):11137-46.
REF 9 Inhibition of m3 muscarinic acetylcholine receptors by local anaesthetics. Br J Pharmacol. 2001 May;133(1):207-16.
REF 10 Differential effects of bupivacaine enantiomers, ropivacaine and lidocaine on up-regulation of cell surface voltage-dependent sodium channels in adrenal chromaffin cells. Brain Res. 2003 Mar 21;966(2):175-84.
REF 11 Local anaesthetic sensitivities of cloned HERG channels from human heart: comparison with HERG/MiRP1 and HERG/MiRP1 T8A. Br J Anaesth. 2004 Jan;92(1):93-101.
REF 12 The anti-nociceptive agent ralfinamide inhibits tetrodotoxin-resistant and tetrodotoxin-sensitive Na+ currents in dorsal root ganglion neurons. Eur J Pharmacol. 2005 Mar 14;510(3):197-208.
REF 13 Carbonic anhydrase inhibitors as anticonvulsant agents. Curr Top Med Chem. 2007;7(9):855-64.
REF 14 Carisbamate, a novel neuromodulator, inhibits voltage-gated sodium channels and action potential firing of rat hippocampal neurons. Epilepsy Res. 2009 Jan;83(1):66-72.
REF 15 In vitro micromass teratogen test: Results from a blind trial of 25 compounds. Toxicol In Vitro. 1990;4(4-5):623-6.
REF 16 Non-specific actions of the non-peptide tachykinin receptor antagonists, CP-96,345, RP 67580 and SR 48968, on neurotransmission. Br J Pharmacol. 1994 Jan;111(1):179-84.
REF 17 Lamotrigine, phenytoin and carbamazepine interactions on the sodium current present in N4TG1 mouse neuroblastoma cells. J Pharmacol Exp Ther. 1993 Aug;266(2):829-35.
REF 18 Fundamental properties of local anesthetics: half-maximal blocking concentrations for tonic block of Na+ and K+ channels in peripheral nerve. Anesth Analg. 1998 Oct;87(4):885-9.

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