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PubMed1986

Cyclic AMP stimulation of Cl- secretion by the opercular epithelium: the basolateral chloride uptake mechanism.

The isolated, short-circuited opercular epithelium of Fundulus heteroclitus, secretes Cl- by a mechanism dependent on the presence of serosal Na+ and inhibited by bumetanide and furosemide. Under serosal Na+-free conditions the active Cl- secretion is abolished. However, subsequent elevations of intracellular cyclic AMP (cAMP) levels with isoproterenol or forskolin stimulated Cl- secretion markedly. This stimulation was unaffected by SITS, DIDS, methazolamide, and HCO-3-free solutions, but was blocked by furosemide and bumetanide. Determinations of relative intracellular 36Cl- levels showed a Na+ dependence of intracellular 36Cl- in epithelia not stimulated by isoproterenol and a Na+ independence of intracellular 36Cl- in isoproterenol stimulated epithelia. In both conditions, the intracellular 36Cl- was bumetanide sensitive. The results indicate that cAMP stimulation of Cl- secretion can occur by a Na+-independent, loop diuretic-inhibitable mechanism, which may be operative even in the presence of Na+. Whether this is a separate Cl- uptake mechanism or a cAMP-induced alteration in the normal Na+-dependent mechanism could not be determined. In either instance, an alternative to the Na+ gradient as a source of energy for Cl- uptake into the cell across the basolateral membrane is required.

Animals↗
PubMed1998

Inhibition and kinetic properties of membrane-bound carbonic anhydrases in rabbit skeletal muscles.

It was the aim of this study to investigate whether the carbonic anhydrases associated with the sarcoplasmic reticulum (SR) and sarcolemmal membranes differ in their kinetic and inhibitory properties. To this end, sarcolemmal and SR membrane vesicle fractions were prepared from rabbit white and red skeletal muscles, the white muscle sarcolemmal fraction (WSL), the red muscle sarcolemmal fraction (RSL), the white muscle SR fraction (WSR), and the red muscle SR fraction (RSR). WSL displayed a specific carbonic anhydrase activity of 22.1 U . ml/mg and RSL of 7.5 U . ml/mg, whereas the SR fractions showed a much lower activity of 0.5 U . ml/mg for WSR and of 2.4 U . ml/mg for RSR. In both SR fractions phase separation experiments with Triton X-114 demonstrated that the carbonic anhydrase activity is due to a membrane-bound enzyme and not due to a cytosolic isozyme. The kinetic properties of carbonic anhydrase from the four distinct membane fractions were evaluated by determination of the Michaelis constant, Km, and of the catalytic centre activity kcat. Km appears to be somewhat lower for SR than for SL. Inhibition constants of SR and SL carbonic anhydrases were determined applying six carbonic anhydrase inhibitors: chlorzolamide, ethoxzolamide, methazolamide, benzolamide, and acetazolamide, and also cyanate. The inhibition constants of the SR fractions were significantly different from those of the corresponding sarcolemmal fractions, indicating that the carbonic anhydrase measured in the SR fractions does not originate from contaminating sarcolemmal membrane vesicles, but appears to represent a distinct carbonic anhydrase associated with the SR membrane.

Animals↗
PubMed1986

Amiloride-sensitive Na+ transport in human red cells: evidence for a Na/H exchange system.

The role of transmembrane pH gradients on the ouabain, bumetanide and phloretin-resistant Na+ transport was studied in human red cells. Proton equilibration through the Jacobs-Stewart cycle was inhibited by the use of DIDS (125 microM) and methazolamide (400 microM). Red cells with different internal pH (pHi = 6.4, 7.0 and 7.8) were prepared and Na+ influx was measured at different external pH (pHo = 6.0, 7.0, 8.0). Na+ influx into acid-loaded cells (pHi = 6.4) markedly increased when pHo was raised from 6.0 to 8.0. Amiloride, a well-known inhibitor of Na+/H+ exchange systems blocked about 60% of the H+-induced Na+ entry, while showing small inhibitory effects in the absence of pH gradients. When pHo was kept at 8.0, the amiloride-sensitive Na+ entry was abolished as pHi was increased from 6.4 to 7.8. Moreover, measurements of H+ efflux into lightly buffered media indicated that the imposition of an inward Na+ gradient stimulated a net H+ efflux which was sensitive to the amiloride analog 5-N-methyl-N-butyl-amiloride. Furthermore, in the absence of a chemical gradient for Na+ (Nai+ = Nao+ = 15 mM, Em = +6.7 mV), an outward H+ gradient (pHi = 6.4, pHo = 8.0) promoted a net amiloride-sensitive Na+ uptake which was abolished at an external pH of 6.0. These findings are consistent with the presence of an amiloride-sensitive Na+/H+ exchange system in human red cells.

Amiloride↗
PubMed1989

Kinetics and stoichiometry of the human red cell Na+/H+ exchanger.

We have investigated the kinetic properties of the human red blood cell Na+/H+ exchanger to provide a tool to study the role of genetic, hormonal and environmental factors in its expression as well as its functional properties in several clinical conditions. The present study reports its stoichiometry and the kinetic effects of internal H+ (Hi) and external Na+ (Nao) in red blood cells of normal subjects. Red blood cells with different cell Na+ (Nai) and pH (pHi) were prepared by nystatin and DIDS treatment of acid-loaded cells. Unidirectional and net Na+ influx were measured by varying pHi (from 5.7 to 7.4), external pH (pHo), Nai and Nao and by incubating the cells in media containing ouabain, bumetanide and methazolamide. Net Na+ influx (Nai less than 2.0 mmol/liter cell, Nao = 150 mM) increased sigmoidally (Hill coefficient 2.5) when pHi fell below 7.0 and the external pHo was 8.0, but increased linearly at pHo 6.0. The net Na+ influx driven by an outward H+ gradient was estimated from the difference of Na+ influx at the two pHo levels (pHo 8 and pHo 6). The H+-driven Na+ influx reached saturation between pHi 5.9 and 6.1. The Vmax had a wide interindividual variation (6 to 63 mmol/liter cell.hr, 31.0 +/- 3, mean +/- SEM, n = 20). The Km for Hi to activate H+-driven Na+ influx was 347 +/- 30 nM (n = 7). Amiloride (1 mM) or DMA (20 microM) partially (59 +/- 10%) inhibited red cell Na+/H+ exchange. The stoichiometric ratio between H+-driven Na+ influx and Na+-driven H+ efflux was 1:1. The dependence of Na+ influx from Nao was studied at pHi 6.0, and Nai lower than 2 mmol/liter cell at pHo 6.0 and 8.0. The mean Km for Nao of the H+-gradient-driven Na+ influx was 55 +/- 7 mM. An increase in Nai from 2 to 20 mmol/liter cell did not change significantly H+-driven net Na+ influx as estimated from the difference between unidirectional 22Na influx and efflux. Na+/Na+ exchange was negligible in acid-loaded, DIDS-treated cells. Na+ and H+ efflux from acid-loaded cells were inhibited by amiloride analogs in the absence of external Na+ indicating that they may represent nonspecific effects of these compounds and/or uncoupled transport modes of the Na+/H+ exchanger. It is concluded that human red cell Na+/H+ exchange performs 1:1 exchange of external Na+ for internal protons, which is partially amiloride sensitive.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed2002

Forskolin-induced clearance of the fluorescent dye sulforhodamine from rat parotid intralobular duct lumen: visualization of the secretory function under a confocal laser scanning microscope.

Cyclic AMP evokes fluid secretion with bicarbonate in exocrine ducts. Clearance of fluorescent dyes from rat parotid intralobular ducts by forskolin was visualized as a fluorescence change in the duct luminal space by optical sectioning under a confocal laser scanning microscope to clarify the secretory function in the ducts. When the isolated rat parotid intralobular duct segments were superfused with membrane-impermeable fluorescent dyes during the experimental period, fluorescent dyes were passively moved into the duct space. Forskolin and isobutylmethylxanthine decreased the fluorescence of anionic dye, sulforhodamine B, and neutral dye, dextran tetramethyl-rhodamine, in the duct space, suggesting that the forskolin-induced clearance of fluorescent dyes might be the result of fluid secretion in the ducts. Methazolamide inhibited a forskolin-induced sustained decrease in duct fluorescence and intracellular acidification. Low concentrations of external Cl?, DIDS, bumetanide and amiloride did not markedly inhibit a forskolin-induced decrease in duct fluorescence. These findings suggest that a major portion of the steady decrease in duct fluorescence by forskolin was related to intracellular HCO3? production, not the uptake mechanism of external Cl?. Glibenclamide, NPPB, DPC and DMA inhibited the forskolin-induced decrease. Forskolin evokes the clearance of fluorescent dyes from duct space possibly due to fluid secretion in rat parotid ducts, associated with secretion through CFTR and DPC-sensitive anion channels of carbonic anhydrase-dependent bicarbonate linked with the Na+/H+ exchange mechanism.

1-Methyl-3-isobutylxanthine↗
PubMed1986

Liver carbonic anhydrase and urea synthesis. The effect of diuretics.

In isolated perfused rat liver, urea synthesis is rapid and reversibly inhibited not only by the well-known carbonic anhydrase inhibitors acetazolamide, methazolamide and ethoxzolamide, but also by diuretics, like xipamide, mefruside, chlortalidone, and chlorothiazide. Furosemide was without effect. Similar to findings with isolated perfused rat liver, acetazolamide inhibits urea synthesis from ammonium ions in normal and cirrhotic human liver slices. Inhibition of urea synthesis by xipamide and acetazolamide is accompanied by a 70% decrease of the cellular citrulline content and the tissue levels of 2-oxoglutarate and citrate, suggesting a block of urea synthesis at a step prior to citrulline formation. At a constant extracellular pH (7.4), inhibition of urea synthesis by xipamide, mefruside and acetazolamide was overcome by increasing the extracellular concentrations of HCO3- and CO2 to above twice the normal values. This shows that inhibition of urea synthesis by these diuretics is not due to an unspecific inhibition of one of the urea cycle enzymes but is due to an inhibition of mitochondrial carbonic anhydrase and therefore due to an impaired HCO3- provision for mitochondrial carbamoylphosphate synthesis. It is concluded that the activity of mitochondrial carbonic anhydrase is required for urea synthesis also in human liver and that several diuretics impair urea synthesis by inhibition of mitochondrial carbonic anhydrase. The pathophysiological significance of these data is discussed with respect to the development of diuretics-induced hyperammonemia and alkalosis in liver disease.

Acetazolamide↗
PubMedDate not supplied

[3H]acetazolamide binding to carbonic anhydrase in normal and transformed cells.

The binding of [3H]acetazolamide (AZ), a carbonic anhydrase (CA) inhibitor, to soluble and particulate forms of CA was investigated. Sources for the assays were purified CA II, adult rat cortical, oligodendrocyte and neuronal enriched preparations; cultured murine glial cells, rat C-6 glioma, rat hepatoma and human glioblastoma cells. CA enzyme activity in the same preparations was also assayed by following change in pH during incubation. A gel permeation chromatographic method was developed to assess [3H]AZ binding to soluble CA, while glass fiber filter vacuum filtration was used for particulate CA binding. Saturable specific binding of [3H]AZ to rat cortical soluble and particulate CA preparations was demonstrated. Computer-assisted data analysis estimated the binding parameters of [3H]AZ to soluble rat cortical CA to be Bmax = 0.38 +/- 0.13 pmol/mg protein and Kd = 34.7 +/- 17.5 nM. The rat cortical particulate fraction Bmax was 2.05 +/- 0.28 pmol/mg protein with a Kd of 107.1 +/- 24.2 nM. Purified bovine CA-II bound 1.15 +/- 0.19 pmol [3H]AZ/mg protein with a Kd of 54.0 +/- 3.4 nM. The pH optima for [3H]AZ binding to soluble and particulate CA was between 6.5 and 7.5. Binding was linear with respect to protein up to 1.0 mg/mL. The particulate fraction bound 3-4 times more [3H]ligand per unit protein than the soluble fraction. Interestingly, no detectable CA enzyme activity or [3H]AZ binding was observed in the soluble or particulate fractions of human glioblastoma, rat C-6 glioma or rat hepatoma cells. Binding of [3H]AZ to other soluble enzymes or proteins was negligible. In competition binding experiments, a rank order of inhibition of [3H]AZ binding to rat cortical CA by established CA inhibitors was: dichlorphenamide greater than acetazolamide greater than or equal to benzolamide greater than methazolamide greater than hydrochlorothiazide greater than or equal to sulfanilamide. [3H]AZ binding was not affected by other classes of pharmacologic characterizing agents. The binding of [3H]AZ to the CA enzyme molecule is highly specific and sensitive and may prove useful in vitro or in situ as a probe for this enzyme.

Acetazolamide↗
PubMed1988

Physiological adaptations of the intertidal rockpool teleost Blennius pholis L., to aerial exposure.

Gas exchange, metabolism, ventilation, circulation and acid-base balance in water and air were investigated in Blennius pholis. The rates of gas exchange in water and air were similar with the RQ remaining around 0.8. Aerial gas exchange was equally divided between the head/gills and the tail region. Ventilatory adaptations involved a reduction in rate in air and the mode of ventilation changed from flow-through to tidal, with closed opercula. A transient bradycardia developed on transition to air before heart frequency (fH) returned to aquatic levels. During aerial exposure PvCO2 rose only by 1 Torr with a concomitant decrease in pH of 0.19 pH-units. At the same time a metabolic acidosis was observed which could not be fully accounted for by the formation of lactic acid in the blood, although tissue lactate levels did not change significantly. No histological evidence was found for the presence of carbonic anhydrase in the epithelial cells of the skin or the oesophagus to aid aerial CO2 excretion. Inhibition of CA activity by addition of methazolamide to blood, however, caused PvCO2 to rise by 3 Torr and pHv to decrease by 0.4 pH unit. It is concluded that B. pholis is physiologically well adapted to aerial exposure through adjustments in ventilation and circulation and that erythrocytic carbonic anhydrase plays a major role in CO2 transfer.

Acid-Base Equilibrium↗
PubMed1983

Efficacy of combining timolol with other antiglaucoma medications.

The ocular hypotensive effects of timolol and a carbonic anhydrase inhibitor (acetazolamide or methazolamide) are partially additive; that is, concurrent administration of these drugs produces a clinically useful reduction in intraocular pressure which is greater than the effect of either medication alone, but less than the arithmetic sum of the effects of the individual drugs. Similarly, concurrent administration of timolol and a miotic agent (pilocarpine, carbachol, or echothiophate iodide) produces a clinically useful response in most glaucoma patients. In contrast, the ocular hypotensive effects of timolol and epinephrine are poorly additive. Only a minority of patients maintain a substantial, longterm reduction in intraocular pressure when timolol is added to a regimen of epinephrine or vice versa. Ophthalmologists prescribing timolol or epinephrine for patients receiving the other drug are urged to use a therapeutic trial to one eye for several weeks to determine the efficacy of concurrent treatment. The addition of timolol to the medical regimen of patients uncontrolled on maximum tolerated antiglaucoma therapy (a miotic agent, epinephrine and a carbonic anhydrase inhibitor) reduces intraocular pressure substantially in one-third to one-half of the cases.

Acetazolamide↗
PubMed1979

Inhibition of the action of anticonvulsants by lithium treatment.

The present study demonstrates that the effectiveness of anticonvulsants significantly decreases following lithium treatment (3 doses of 50 mg/kg of LiCl given every 12 hr). The anticonvulsant action of phenytoin, phenobarbital and of 3 carbonic anhydrase inhibitors: methazolamide, acetazolamide, ethoxzolamide, was assessed in rats subjected to maximal electroshock. In a chronic study on tolerance development to the anticonvulsant action of acetazolamide, lithium treatment (10 mg/kg per day) has been shown to inhibit gradually the action of acetazolamide. These results are consistent with the hypothesis that norepinephrine and dopamine are involved in the action of anticonvulsants.

Animals↗
PubMed2006

Topical dorzolamide for the treatment of cystoid macular edema in patients with retinitis pigmentosa.

PURPOSE: To determine if topical dorzolamide, as observed with the use of systemic acetazolamide and methazolamide, would be effective in treating cystoid macular edema (CME) in patients with retinitis pigmentosa (RP). DESIGN: Prospective, nonrandomized clinical trial. METHODS: setting: Institutional. patients: Fifteen patients with CME and RP. intervention: A baseline visual acuity and optical coherence tomography (OCT) measurements were obtained in all patients. Each one of them was then treated with topical dorzolamide, three times a day, for at least four weeks in both eyes. main outcome measures: Significant decrease in "foveal thickness" (more than 16%) and "foveal zone thickness" (more than 11%), as measured by OCT. RESULTS: Thirteen (87%) of 15 patients showed a significant decrease in retinal thickness in at least one eye after use of topical dorzolamide for at least four weeks. Five patients (33%) demonstrated improvement in both eyes. All patients, except one, who responded showed the effect within four weeks, but were monitored for a period of two to nine months (average 4.5 months). Four patients (31%) who showed an initial improvement in macular edema showed worsening with continued treatment. CONCLUSIONS: The present study documents the potential efficacy of topical dorzolamide for treating CME in patients with RP. We observed that some patients may show a "rebound phenomenon" with continued use of the medication; hence, there is a need for careful follow-up in patients being treated.

Administration, Topical↗
PubMed2006

Expression, purification, kinetic, and structural characterization of an alpha-class carbonic anhydrase from Aedes aegypti (AaCA1).

Carbonic anhydrases (CAs) are zinc-containing metalloenzymes that catalyze the interconversion of carbon dioxide and bicarbonate. The alpha-class CAs are found predominantly in vertebrates, but they are also expressed in insects like mosquitoes. Recently, an alpha-CA from the midgut of Aedes aegypti larvae (AaCA1) was identified, cloned, and subsequently shown to share high sequence homologous to human CA I (HCA I). This paper presents the bacterial expression, purification, and kinetic characterization of the soluble CA domain of AaCA1. The data show AaCA1 is a highly active CA that displays inhibition by methazolamide and ethoxzolamide with nM affinity. Additionally, a homology model of AaCA1, based on the crystal structure of HCA I, is presented and the overall structure, active site, and surface charge properties are compared to those of HCA I and II. Measurements of catalysis show that AaCA1 is more like HCA II in terms of proton transfer, but more similar to HCA I in terms of conversion of carbon dioxide to bicarbonate, and these differences are rationalized in terms of structure. These results also indicate that amino acid differences in the active site of AaCA1 compared to human CAs could be used to design specific CA inhibitors for the management of mosquito populations.

Aedes↗
PubMed2004

Carbonic anhydrase inhibitors: aromatic and heterocyclic sulfonamides incorporating adamantyl moieties with strong anticonvulsant activity.

A series of aromatic/heterocyclic sulfonamides incorporating adamantyl moieties were prepared by reaction of aromatic/heterocyclic aminosulfonamides with the acyl chlorides derived from adamantyl-1-carboxylic acid and 1-adamantyl-acetic acid. Related derivatives were obtained from the above-mentioned aminosulfonamides with adamantyl isocyanate and adamantyl isothiocyanate, respectively. Some of these derivatives showed good inhibitory potency against two human CA isozymes involved in important physiological processes, CA I, and CA II, of the same order of magnitude as the clinically used drugs acetazolamide and methazolamide. The lipophilicity of the best CA inhibitors was determined and expressed as their experimental log k' IAM and theoretical ClogP value. Their lipophilicity was propitious with the crossing of the blood-brain barrier (log k' > IAM > 1.35). The anticonvulsant activity of some of the best CA inhibitors reported here has been evaluated in a MES test in mice. After intraperitoneal injection (30 mg kg(-1)), compounds A8 and A9 exhibited a high protection against electrically induced convulsions (> 90%). Their ED50 was 3.5 and 2.6 mg kg(-1), respectively.

Animals↗
PubMed2004

Carbonic anhydrase inhibitors: E7070, a sulfonamide anticancer agent, potently inhibits cytosolic isozymes I and II, and transmembrane, tumor-associated isozyme IX.

E7070 [N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide] is an anticancer drug candidate under clinical development for the treatment of several types of cancers. We prove here that this compound also acts as a potent carbonic anhydrase (CA) inhibitor. Similarly to the clinically used drugs acetazolamide, methazolamide and topiramate, E7070 showed inhibition constants in the range of 15-31nM against isozymes I, II and IX, being slightly less effective as a CA IV inhibitor (K(i) of 65nM). The X-ray crystal structure of the adduct of hCA II with E7070 revealed unprecedented interactions between the inhibitor and the active site, with three different conformations of the chloroindole fragment of the inhibitor interacting with different amino acid residues/water molecules of the enzyme. A superimposition of these conformations with those of other sulfonamide/sulfamate CA inhibitors indicated that similar regions of the hCA II active site could be involved in the interaction with inhibitors.

Animals↗
PubMed2004

Carbonic anhydrase inhibitors: N-(p-sulfamoylphenyl)-alpha-D-glycopyranosylamines as topically acting antiglaucoma agents in hypertensive rabbits.

A series of N-(p-sulfamoylphenyl)-alpha-D-glycopyranosylamines was prepared by reaction of sulfanilamide with different monosaccharides in the presence of ammonium chloride. The new compounds were investigated for inhibition of the metallo-enzyme carbonic anhydrase (CA, EC 4.2.1.1), involved in aqueous humor secretion within the mammalian eye. Isozymes CA I and CA II were strongly inhibited by some of these compounds, which showed inhibition constants in the range of 510-1200 nM against CA I and 10-25 nM against CA II, similarly to clinically used sulfonamides, such as acetazolamide, methazolamide, dichlorophenamide, dorzolamide and brinzolamide. The presence of sugar moieties in these molecules induced an enhanced water solubility as compared to other sulfonamides. In hypertensive rabbits (a widely used animal model of glaucoma), two of the new compounds showed strong and long-lasting intraocular pressure (IOP) lowering, being more effective than dorzolamide and brinzolamide, the two clinically used, topically acting antiglaucoma sulfonamides with CA inhibitory properties.

Administration, Topical↗
PubMed2004

Carbonic anhydrase inhibitors: the first QSAR study on inhibition of tumor-associated isoenzyme IX with aromatic and heterocyclic sulfonamides.

QSAR study on the tumor-associated transmembrane carbonic anhydrase IX (CA IX) isoenzyme has been made using a large pool of distance-based topological indices : W, Sz, PI (0)chi, (1)chi, (2)chi,(0)chi(v), (1)chi(v), (2)chi(v). A combined set of 32 aromatic and heterocyclic compounds, including the six clinically used derivatives: acetazolamide, methazolamide, ethoxyzolamide, dichlorophenamide, dorzolamide, and brinzolamide are used for this purpose. The results have shown that the inhibition of the tumor-associated isoenzyme IX with aromatic and heterocyclic sulfonamides can be modeled excellently in multiparametric regression after introduction of indicator parameters. The predictive power of the models is discussed using probable error of correlation (PE), variance-inflation factor (VIF), and cross-validation parameters: PRESS, SSY, r(2) (cv) (S) PRESS, and PSE. This is the first report on QSAR study on inhibition of tumor-associated isoenzyme IX.

Antigens, Neoplasm↗
PubMed2004

Carbonic anhydrase inhibitors. Inhibition of cytosolic isozyme XIII with aromatic and heterocyclic sulfonamides: a novel target for the drug design.

The inhibition of the newly discovered cytosolic carbonic anhydrase isozyme XIII (CA XIII) has been investigated with a series of aromatic and heterocyclic sulfonamides, including some of the clinically used derivatives, such as acetazolamide, methazolamide, dichlorophenamide, dorzolamide, and valdecoxib. Inhibition data for the physiologically relevant isozymes I and II (cytosolic forms) and the tumor associated isozyme IX (transmembrane) were also provided for comparison. A very interesting and unusual inhibition profile against CA XIII with these sulfonamides has been observed. The clinically used compounds (except valdecoxib, which was a weak CA XIII inhibitor) potently inhibit CA XIII, with Ki's in the range of 17-23 nM, whereas sulfanilamide, halogenated sulfanilamides, homosulfanilamide, 4-aminoethylbenzenesulfonamide, and orthanilamide were slightly less effective, with Ki's in the range of 32-56 nM. Several low nanomolar (Ki's in the range of 1.3-2.4 nM) CA XIII inhibitors have also been detected, all of them belonging to the sulfanilyl-sulfonamide type of inhibitors, of which aminobenzolamide is the best known representative. Because CA XIII is an active isozyme predominantly expressed in salivary glands, kidney, brain, lung, gut, uterus, and testis, where it probably plays an important role in pH regulation, its inhibition by sulfonamides may lead to novel therapeutic applications for this class of pharmacological agents.

Amino Acid Sequence↗
PubMed2004

Carbonic anhydrase inhibitors. Design of anticonvulsant sulfonamides incorporating indane moieties.

A series of aromatic sulfonamides incorporating indane moieties were prepared starting from commercially available 1- and 2-indanamine, and their activity as inhibitors of two carbonic anhydrase (CA, EC 4.2.1.1) isozymes, hCA I and II was studied. The new sulfonamides incorporating acetamido, 4-chloro-benzoyl, valproyl, tetra-, and pentafluorobenzoyl moieties acted as very potent inhibitors of the slow red blood cell isozyme hCA I (K(i)s in the range of 1.6-8.5 nM), which usually has a lower affinity for such inhibitors, as compared to isozyme II. Some derivatives also showed excellent hCA II inhibitory properties (K(i)s in the range of 2.3-12 nM), but the anticonvulsant activity of these sulfonamides was rather low as compared to that of other sulfonamide/sulfamate CA inhibitors, such as methazolamide. Furthermore, the 2-amino/acetamido-indane-5-sulfonic acids prepared during this work also showed interesting CA inhibitory properties, with inhibition constants in the range of 43-89 nM against the two isozymes, being among the most potent sulfonic acid CA inhibitors reported so far.

Animals↗