Zonisamide

Zonisamide is a broad-spectrum sulfonamide antiepileptic agent.¹ It selectively blocks the repeated firing of sodium channels (IC₅₀ = 2 μg/ml) at low concentrations in mouse embryo spinal cord neurons, and it blocks spontaneous channel firing at concentrations above 10 μg/ml.² In rat cerebral cortex neurons, zonisamide (1-1000 μM) dose-dependently blocks T-type calcium channels with a maximum reduction of 60% of the calcium current.³ Zonisamide inhibits recombinant H. pylori carbonic anhydrase (CA) and human CA isoforms I, II, and V with K_i values of 218, 56, 35, and 21 nM, respectively.^4,5 Zonisamide has anticonvulsant activity in rats, rabbits, dogs, and mice with a potency similar to phenobarbital (Item No. 9001494) and carbamazepine in maximal electroshock seizure (MES) models.¹ In mice, it has anticonvulsant activity against MES and pentylenetetrazole-induced maximal and minimal seizures with median effective doses of 19.6, 9.3, and >500 mg/kg, respectively. Zonisamide (10-100 mg/kg, p.o.) dose-dependently prevents reduction of dopamine (Item No. 21992), homovanillic acid (HVA), and dihydroxyphenyl acetic acid (DOPAC) levels and the elevation of the dopamine turnover rate induced by MPTP in mouse striatum. Formulations containing zonisamide have been used in the treatment of partial seizures in adults with epilepsy.

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1. Masuda, Y., Ishizaki, M., and Shimizu, M. Zonisamide: Pharmacology and clinical efficacy in epilepsy. CNS Drug Rev. 4(4), 341-360 (1998).

2. Rock, D.M., Macdonald, R.L., and Taylor, C.P. Blockade of sustained repetitive action potentials in cultured spinal cord neurons by zonisamide (AD 810, CI 912), a novel anticonvulsant. Epilepsy Res. 3(2), 138-143 (1989).

3. Suzuki, S., Kawakami, K., Nishimura, S., et al. Zonisamide blocks T-type calcium channel in cultured neurons of rat cerebral cortex. Epilepsy Res. 12(1), 21-27 (1992).

4. Nishimori, I., Vullo, D., Minakuchi, T., et al. Carbonic anhydrase inhibitors: Cloning and sulfonamide inhibition studies of a carboxyterminal truncated α-carbonic anhydrase from Helicobacter pylori. Bioorg. Med. Chem. Lett. 16(8), 2182-2188 (2006).

5. De Simone, G., Di Fiore, A., Menchise, V., et al. Carbonic anhydrase inhibitors. Zonisamide is an effective inhibitor of the cytosolic isozyme II and mitochondrial isozyme V: Solution and X-ray crystallographic studies. Bioorg. Med. Chem. Lett. 15(9), 2315-2320 (2005).