Abstract
A small library of indanesulfonamides was screened for the inhibition of the human carbonic anhydrase (CA, EC 4.2.1.1) isoforms involved in neuronal excitation, that is, isoforms VII, XII and XIV. These CA isoforms are becoming interesting target for the design of agents useful for the treatment of epilepsy. The inhibition pattern of these indanesulfonamide compounds towards these three isoforms was excellent, with many nanomolar inhibitors detected (K(I)s in the range of 0.78-10 nM against hCA VII; 0.32-56 nM against hCA XII, and 0.47-1030 nM against hCA XIV, respectively). The maximal electroshock seizure (MES) test performed on mice showed a good anticonvulsant activity for some compounds which protected the mice against convulsions in the 50-62.5% range at a dose of 50 mg/kg. In parallel, the blood-brain barrier passive permeation of these sulfonamides was also estimated by using a computational approach.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anticonvulsants / chemical synthesis
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Anticonvulsants / chemistry
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Anticonvulsants / pharmacology*
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Blood-Brain Barrier / drug effects
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Blood-Brain Barrier / physiology
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Carbonic Anhydrase Inhibitors / chemical synthesis
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Carbonic Anhydrase Inhibitors / chemistry
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Carbonic Anhydrase Inhibitors / pharmacology*
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Carbonic Anhydrases / drug effects*
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Carbonic Anhydrases / metabolism
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Central Nervous System / drug effects
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Central Nervous System / physiology
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Computer Simulation
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Electroshock
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Humans
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Isoenzymes / antagonists & inhibitors*
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Isoenzymes / metabolism
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Male
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Mice
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Mice, Inbred Strains
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Models, Animal
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Models, Chemical
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Molecular Structure
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / metabolism
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Reproducibility of Results
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Seizures / prevention & control*
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Anticonvulsants
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Carbonic Anhydrase Inhibitors
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Isoenzymes
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Recombinant Proteins
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Carbonic Anhydrases