Carbonic anhydrase inhibitors. Inhibition of the membrane-bound human and bovine isozymes IV with sulfonamides.
An inhibition study of the human and bovine membrane-associated isozymes of carbonic anhydrase (CA, EC 4.2.1.1), hCA IV and bCA IV, with a series of sulfonamides and sulfamates, some of which are widely clinically used, such as acetazolamide, methazolamide, ethoxzolamide, topiramate, dorzolamide, dichlorophenamide, celecoxib, and valdecoxib among others, is reported. In contrast to bCA IV, which is generally strongly inhibited by most of these derivatives, hCA IV has a rather different inhibition profile. Several of these compounds such as acetazolamide, ethoxzolamide, and bromosulfanilamide are potent hCA IV inhibitors (K(i)'s of 74-93 nM), others, such as celecoxib and some halogenated sulfanilamides are medium potency inhibitors (K(i)'s of 450-880 nM) whereas most of them are weak hCA IV inhibitors (methazolamide: 6.2 microM; dorzolamide 8.5 microM; topiramate 4.9 microM; dichlorophenamide: 15.3 microM). The hCA IV/bCA IV inhibition ratios for all the investigated compounds ranged between 1.05 (for acetazolamide) and 198.37 (for dorzolamide). Based on these results, we doubt that hCA IV is indeed one of the main contributors to the intraocular pressure (IOP) lowering effects of sulfonamide CA inhibitors, in addition to hCA II, as hypothesized earlier by Maren et al. (Mol. Pharmacol.1993, 44, 901-906). Indeed, both the very good hCA IV inhibitors (acetazolamide and ethoxzolamide) as well as the quite weak hCA IV inhibitors (methazolamide, dorzolamide, or dichlorophanamide) are effective in lowering IOP when administered either systemically or topically. The membrane-associated isozyme which probably is critical for aqueous humor secretion is hCA XII and not hCA IV.
Innocenti
Alessio
A
Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino (Firenze), Italy.
Firnges
Michael A
MA
Antel
Jochen
J
Wurl
Michael
M
Scozzafava
Andrea
A
Supuran
Claudiu T
CT
D000818:Animals; D030741:Carbonic Anhydrase IV / Q000037:antagonists & inhibitors*; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007700:Kinetics; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology; D013451:Sulfonic Acids / Q000737:chemistry / Q000494:pharmacology
D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D013449:Sulfonamides; D013451:Sulfonic Acids; C005741:sulfamic acid; D030741:Carbonic Anhydrase IV