Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0595921 (intraocular pressure)
 11,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Carbonic anhydrase (CA) activity plays an important role in controlling aqueous humor production in the eye and in regulating intraocular pressure. Prior studies identified the soluble isozymes CA II and CA I in the human eye and also suggested a distinct membrane-associated CA. We used an antibody to CA IV, the membrane-anchored isozyme from human lung, to study CA IV in eye tissues and to compare its distribution with that of CA II. We found intense immunostaining for CA IV associated with endothelial cells of one specific uveal capillary bed, the choriocapillaris. CA IV was not detected in endothelial cells of the contiguous capillaries of the iris or in endothelial cells of other vessels. Immunoreactivity for CA IV was also intense in epithelial and fiber cells of the lens but was not detectable in the neuroretina, the ciliary process (except for capillaries), and the cornea, all sites where immunostaining with anti-CA II antibody was intense. These studies indicate that the membrane-associated CA in human eye, which was suspected from histochemical studies, is CA IV. Defining the physiological role of this ocular isozyme remains a challenge.
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PMID:Localization of carbonic anhydrase IV in a specific capillary bed of the human eye. 190 14

Carbonic anhydrase inhibitors (CAIs) lower intraocular pressure by reducing aqueous flow. It has been thought that this pharmacologic reduction of aqueous flow is mediated by the ciliary epithelium, but it is not known whether this cellular action is effected by inhibition of the membranal (CA IV) and/or cytosolic (CA II) carbonic anhydrases of the ciliary epithelium. The isolated ciliary epithelial bilayer maintains its anatomic and functional polarity and generates a transepithelial potential difference (TEP) in an Ussing type chamber. Depletion of HCO3-, accomplished either with an HCO3(-)-free solution bathing the epithelial bilayer, or, with addition of freely permeant CAIs to HCO3(-)-containing media, (from either the PE or NPE side of the bilayer) depolarizes the preparation. Addition of CAIs to an HCO3(-)-depleted preparation has no further effect, indicating the specific action of the CAIs. The CAI, 2-p-NH2 benzenesulfonamido-1,3,4,-thiadiazole-5-SO2NH2, linked to polybutadiene maleic acid yields an impermeant polymer of 20000 Da with no loss of activity. At 45 microM this impermeant polymer caused a 60% increase in the SCC, seen only when the compound was applied to the NPE side of the bilayer. This latter result indicates an effect from inhibition of CA IV in the basolateral membranes of the NPE. Thus there are probably two different cellular actions of CAIs upon the ciliary epithelium to reduce aqueous inflow, cytoplasmic and membranal. The action of NPE basolateral membranal CA IV is probably linked to the chloride/bicarbonate exchanger.
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PMID:Membrane carbonic anhydrase (IV) and ciliary epithelium. Carbonic anhydrase activity is present in the basolateral membranes of the non-pigmented ciliary epithelium of rabbit eyes. 879 59

Reaction of 20 aromatic/heterocyclic sulfonamides containing a free amino, imino, hydrazino or hydroxyl group, with picolinic acid in the presence of carbodiimide derivatives afforded a series of water-soluble (as hydrochloride or triflate salts) compounds. The new derivatives were assayed as inhibitors of three carbonic anhydrase (CA) isozymes, CA I, II (cytosolic forms) and IV (membrane-bound form). Efficient inhibition was observed against all three isozymes, but especially against CA II and CA IV (in nanomolar range), the two isozymes known to play a critical role in aqueous humor secretion within the ciliary processes of the eye. Some of the best inhibitors synthesized were applied as 2% water solutions directly into the eye of normotensive or glaucomatous albino rabbits. Very strong intraocular pressure (IOP) lowering was observed for many of them, and the active drug was detected in eye tissues and fluids. This result prompted us to reanalyze the synthetic work done by other groups for the design of water soluble, topically effective antiglaucoma sulfonamides. According to these researchers, the IOP lowering effect is due to the intrinsic nature of the specific heterocyclic sulfonamide considered, among which the thienothiopyran-2-sulfonamide derivatives represent the best studied case. Indeed, the first agents developed for such applications, such as dorzolamide, are derivatives of this ring system. In order to prove that the tail (in this case the picolinoyl moiety) conferring water solubility to a sulfonamide CA inhibitor is critically important for its topical effectiveness, similarly to the ring to which the sulfonamido group is grafted, we also prepared a dorzolamide derivative to which the picolinoyl moiety was attached. This new compound is more water soluble than dorzolamide (as hydrochloride salt), behaves as a strong CA II inhibitor, and acts similarly to the parent derivative in lowering IOP in experimental animals. Thus, it seems that the tail conferring water solubility is more important for topical activity as antiglaucoma drug, than the heterocyclic/aromatic ring to which the sulfonamido moiety is grafted.
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PMID:Carbonic anhydrase inhibitors. Part 71. Synthesis and ocular pharmacology of a new class of water-soluble, topically effective intraocular pressure lowering sulfonamides incorporating picolinoyl moieties. 1042 82

Reaction of twenty aromatic/heterocyclic sulfonamides containing a free amino, imino, hydrazino or hydroxyl group, with isonicotinoyl chloride afforded a series of water-soluble compounds (as hydrochloride or triflate salts). The new derivatives were examined as inhibitors of three carbonic anhydrase (CA) isozymes, CA I, II (cytosolic forms) and IV (membrane-bound form). Efficient inhibition was observed against all three isozymes, but especially against CA II and CA IV (K(I) in the nanomolar range), the two isozymes known to play a critical role in aqueous humor secretion within the ciliary processes of the eye. Some of the most potent inhibitors synthesized were applied as 2% water solutions directly into the eye of normotensive or glaucomatous albino rabbits. Very strong intraocular pressure (IOP) lowering was observed for many of them, and the active drug was detected in eye tissues and fluids. According to others the IOP lowering effect of topically effective antiglaucoma sulfonamides is due to the intrinsic nature of the specific heterocyclic sulfonamide considered, among which the thienothiopyran-2-sulfonamide derivatives represent the best studied case e.g. dorzolamide. In order to prove that the tail (in this case the isonicotinoyl moiety) conferring water solubility to a sulfonamide CA inhibitor is more important than the ring to which the sulfonamido group is grafted a dorzolamide derivative to which the isonicotinoyl moiety was attached was also prepared. This new compound is more water soluble than dorzolamide (as hydrochloride salt), behaves as a strong CA II inhibitor and acts similarly to the parent derivative in lowering IOP in experimental animals. Thus, it seems that the tail conferring water solubility is more important for topical activity as an antiglaucoma drug than the heterocyclic/aromatic ring to which the sulfonamido moiety is attached.
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PMID:Carbonic anhydrase inhibitors. Water-soluble, topically effective intraocular pressure lowering agents derived from isonicotinic acid and aromatic/heterocyclic sulfonamides: is the tail more important than the ring? 1053 79

Reaction of 26 aromatic/heterocyclic sulfonamides containing amino, imino, hydrazino or hydroxyl groups with N-tert-butoxycarbonyl-gamma-aminobutyric acid (Boc-GABA; Boc=t-butoxycarbonyl) in the presence of carbodiimide derivatives, afforded after removal of the protecting group, a series of water-soluble compounds (as salts of strong acids, such as hydrochloric, trifluoroacetic or trifluoromethane sulfonic). The new derivatives were assayed as inhibitors of the zinc enzyme carbonic anhydrase (CA), and more precisely of three of its isozymes, CA I, II (cytosolic forms) and IV (membrane-bound form), involved in important physiological processes. Some of the new compounds effectively inhibited CA II and CA IV (in the nanomolar range), the two isozymes known to play a critical role in aqueous humor secretion within the ciliary processes of the eye. Some of the best inhibitors obtained as described above were applied as 2% water solutions into the eye of normotensive or glaucomatous albino rabbits, when strong and long-lasting intraocular pressure (IOP) lowering has been evidenced. Thus, the amino acyl tail conferring water solubility to these sulfonamides, coupled with their strong enzyme inhibitory properties and balanced lipid solubility seem to be the key factors for obtaining compounds with effective topical antiglaucoma activity from the class of the carbonic anhydrase inhibitors.
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PMID:Carbonic anhydrase inhibitors. Part 79. Synthesis of topically acting sulfonamides incorporating GABA moieties in their molecule, with long-lasting intraocular pressure-lowering properties. 1062 Jul 31

Reaction of 26 aromatic/heterocyclic sulfonamides containing amino, imino, hydrazino or hydroxyl groups with N-tert-butyloxycarbonyl-beta-alanine (Boc-beta-ala; Boc = t-butoxycarbonyl) in the presence of carbodiimide derivatives afforded, after removal of the protecting group, a series of water-soluble compounds (as salts of strong acids, such as hydrochloric, trifluoroacetic or trifluoromethane sulfonic). The new derivatives were assayed as inhibitors of the zinc enzyme carbonic anhydrase (CA), and more precisely of three of its isozymes, CA I, II (cytosolic forms) and IV (membrane-bound form), involved in important physiological processes. Good inhibition was observed against all three isozymes, but especially against CA II and CA IV (in the nanomolar range), the two isozymes known to play a critical role in aqueous humour secretion within the ciliary processes of the eye. Some of the best inhibitors synthesized were applied as 2% aqueous solutions into the eyes of normotensive or glaucomatous albino rabbits, when strong and long-lasting intraocular pressure (IOP) lowering was observed with many of them. Thus, the amino acyl groups conferring water solubility to these sulfonamide CA inhibitors, coupled with their strong enzyme inhibitory properties and balanced lipid solubility seem to be the key factors for obtaining compounds with effective topical antiglaucoma activity.
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PMID:Carbonic anhydrase inhibitors - part 78(#). Synthesis of water-soluble sulfonamides incorporating beta-alanyl moieties, possessing long lasting-intraocular pressure lowering properties via the topical route. 1078 57

Reaction of the acyl chlorides of phthalimido-glycine or phthalimido-beta-alanine with 5-amino-1,3,4-thiadiazole-2-sulfonamide afforded after hydrazinolysis and deprotection of the phthalimido group the corresponding 5-(omega-aminoalkylcarboxamido)-1,3,4-thiadiazole-2-sulfonamides. Reaction of 5-(beta-aminoethylcarboxamido)-1,3,4-thiadiazole-2-sulfonamide with sulfonyl halides or acyl halides afforded a series of compounds possessing beta-alkyl/arylsulfonyl/carbonylamidoethylcarboxamido moieties in the 5 position of the thiadiazole-2-sulfonamide ring. The new derivatives were efficient inhibitors of three carbonic anhydrase (CA) isozymes, CA I, II (cytosolic forms) and IV (membrane-bound form), but especially against CA II and CA IV (in nanomolar range), the two isozymes known to play an important role in aqueous humor secretion within the ciliary processes of the eye. Some of the synthesized inhibitors possessed good water solubility (as hydrochlorides or sodium salts) and were applied as 2% solutions directly into the eye of normotensive or glaucomatous albino rabbits. Very strong intraocular pressure (IOP) lowering was observed for many of them for prolonged periods of 1-2 h, and the active drug was detected in eye tissues and fluids indicating that the antiglaucoma effect is due to CA inhibition within the eye.
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PMID:Carbonic anhydrase inhibitors. Synthesis of topically effective intraocular pressure lowering agents derived from 5-(omega-aminoalkylcarboxamido)-1,3,4-thiadiazole-2-sulfonamide. 1085 Sep 53

Reaction of the acyl chlorides of phthalimido-glycine or phthalimido-beta-alanine with 5-amino-1,3,4-thiadiazole-2-sulfonamide afforded after hydrazinolysis and deprotection of the phthalimido group the corresponding 5-(omega-aminoalkylcarboxamido)-1,3,4-thiadiazole-2-sulfonamides. Reaction of 5-(beta-aminoethylcarboxamido)-1,3,4-thiadiazole-2-sulfonamide with sulfonyl halides or acyl halides afforded a series of compounds possessing beta-alkyl/arylsulfonyl/carbonylamidoethylcarboxamido moieties in the 5 position of the thiadiazole-2-sulfonamide ring. The new derivatives were efficient inhibitors of three carbonic anhydrase (CA) isozymes, CA I, II (cytosolic forms) and IV (membrane-bound form), but especially against CA II and CA IV (in nanomolar range), the two isozymes known to play an important role in aqueous humor secretion within the ciliary processes of the eye. Some of the synthesized inhibitors possessed good water solubility (as hydrochlorides or sodium salts) and were applied as 2% solutions directly into the eye of normotensive or glaucomatous albino rabbits. Very strong intraocular pressure (IOP) lowering was observed for many of them for prolonged periods of 1-2 h, and the active drug was detected in eye tissues and fluids indicating that the antiglaucoma effect is due to CA inhibition within the eye.
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PMID:Carbonic Anhydrase Inhibitors. Synthesis of Topically Effective Intraocular Pressure Lowering Agents Derived from 5-(omega-Amino- alkylcarboxamido)-1,3,4-Thia- diazole-2-Sulfonamide. 1093 32

Important physiological and physio-pathological functions are played by several carbonic anhydrase (CA, EC 4.2.1.1) isozymes, which are strongly inhibited by aromatic and heterocyclic sulfonamides. Here we report several new types of such sulfonamides, incorporating furan-, thiophene- and pyrrole-carboxamide moieties in their molecules. Some of these compounds showed very good CA II and CA IV inhibitory properties. with affinities for the enzymes in the low nanomolar range. Due to their relatively low water solubility, some of the most active CA II inhibitors reported here have been formulated as aqueous suspension for topical administration as antiglaucoma agents. in normotensive and glaucomatous rabbits. The derivatives incorporating furan- and pyrrole-carboxamide moieties (but not the corresponding thiophene-substituted derivatives), showed effective and long-lasting intraocular pressure (IOP) lowering both in normotensive as well as glaucomatous animals, with potencies superior to dorzolamide and brinzolamide, the two available topically acting sulfonamide drugs. This is the first example of non-water soluble sulfonamides that significantly lower IOP, being thus similar with the recently introduced drug brinzolamide, which belongs to a completely different chemical family of antiglaucoma sulfonamides.
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PMID:Carbonic anhydrase inhibitors: sulfonamides incorporating furan-, thiophene- and pyrrole-carboxamido groups possess strong topical intraocular pressure lowering properties as aqueous suspensions. 1100 59

Sulfonamides incorporating cis-5-norbornene-endo-3-carboxy-2-carboxamido moieties in their molecules were prepared by reaction of cis-5-norbornene-endo-2,3-dicarboxylic anhydride with aromatic/heterocyclic sulfonamides possessing free amino, hydrazino, or imino groups. Some of these compounds showed very good CA II and CA IV inhibitory properties, with affinities for the enzymes in the low nanomolar range. Some of the most active CA II inhibitors reported here have been formulated as aqueous solutions for topical administration as antiglaucoma agents in normotensive rabbits. Some of the derivatives incorporating cis-5-norbornene-endo-3-carboxy-2-carboxamido and aromatic sulfonamide moieties (as sodium salts) showed effective and longer lasting intraocular pressure (IOP) lowering as compared to dorzolamide, a widely used topical antiglaucoma drug. Compounds incorporating cis-5-norbornene-endo-2,3-carboximido moieties, although stronger in vitro CA inhibitors as compared to the corresponding cis-5-norbornene-endo-3-carboxy-2-carboxamido-;derivatives, showed no topical IOP lowering properties, probably due to their very poor water solubility.
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PMID:Carbonic anhydrase inhibitors: synthesis and inhibition against isozymes I, II and IV of topically acting antiglaucoma sulfonamides incorporating cis-5-norbornene-endo-3-carboxy-2-carboxamido moieties. 1134 80


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