Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0847097 (acidity)
 15,165 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Almost all of the existing known antagonists at the glycine site of the N-methyl-D-aspartate (NMDA) receptor have a low propensity for crossing the blood-brain barrier. It has been suggested that in many cases this may be due to the presence of a carboxylic acid which is a common feature of most of the potent full antagonists at this receptor. In this study, 2-aryl-1H-pyrazolo[3,4-c]quinoline-1,4(2H)-diones were found to have high-affinity binding at the glycine receptor. In particular, structure-activity studies identified 7-chloro-3,5-dihydro-2-(4-methoxyphenyl)-1H-pyrazolo[3,4-c]quinoline- 1,4(2H)-dione as the most potent of a series of analogues with an IC50 of 3.3 nM. The measured pKa values in this class of compounds (typically 4.0) indicate they are of equivalent acidity to carboxylic acids. Functional antagonism was demonstrated by inhibition of NMDA-evoked responses in rat cortical slices. Anticonvulsant activity in DBA/2 mice was achieved after dosing by direct injection into the cerebral ventricles, but no activity was seen after systemic administration, suggesting low brain penetration with this class of antagonists.
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PMID:Identification of 3,5-dihydro-2-aryl-1H-pyrazolo[3,4-c]quinoline-1,4(2H)-diones as novel high-affinity glycine site N-methyl-D-aspartate antagonists. 778 55

3,4-Dihydro-2(1H)-quinolones, evolved from 2-carboxy-1,2,3,4,- tetrahydroquinolines and 3-carboxy-4-hydroxy-2(1H)-quinolones, have been synthesized and evaluated in vitro for antagonist activity at the glycine site on the NMDA receptor and for AMPA [(RS)-alpha-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid] antagonist activity. Generally poor potency at the glycine site is observed when a variety of electron-withdrawing substituents are attached to the 3-position of 3,4-dihydro-2(1H)-quinolones. The analogues 5-9 (IC50 values > 100 microM, Table I) exist largely in the 3,4-dipseudoaxial conformation (as evidenced by 1H NMR spectra), whereas the 3-cyano derivative (10, IC50 = 12.0 microM) has a relatively high population of the 3-pseudoequatorial conformer. The 3-nitro analogue (4, IC50 = 1.32 microM) has a pKa approximately 5 and thus exists at physiological pH as an anion with the nitro group planar to the quinolone ring. The general requirement of acidity for high affinity binding at the glycine/NMDA site is supported with the good activity of the other 3-nitro derivatives (13-21), all of which are deprotonated at physiological pH. The 3-nitro-3,4-dihydro-2(1H)-quinolones and 2-carboxy-1,2,3,4-tetrahydroquinolines show quite different structure-activity relationships at the 4-position. The unselective excitatory amino acid activity of 21 is comparable with 6,7-dichloro-quinoxaline-2,3-dione and 6,7-dichloroquinoxalic acid and this suggests similarities in their modes of binding to excitatory amino acid receptors. The broad spectrum excitatory amino acid antagonist activity of the 4-unsubstituted analogue 21 (KbNMDA = 6.7 microM, KbAMPA = 9.2 microM) and the glycine/NMDA selectivity of the other 3-nitro derivatives allows the proposal of a model for AMPA receptor binding which differs from the glycine binding pharmacophore in that there is bulk intolerance adjacent to the 4-position. Compound 21 (L-698,544) is active (ED50 = 13.2 mg/kg) in the DBA/2 mouse anticonvulsant model and is the most potent combined glycine/NMDA-AMPA antagonist yet reported, in vivo, and may prove to be a useful pharmacological tool.
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PMID:3-Nitro-3,4-dihydro-2(1H)-quinolones. Excitatory amino acid antagonists acting at glycine-site NMDA and (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. 823 Jan 30

Mucins in the gastrointestinal tract of Rhinolophus ferrumequinum were investigated by histochemistry and lectin histochemistry to evaluate morphofunctional variations of different regions and their possible physiological and evolutionary implications. Histochemical methods included periodic acid-Schiff (PAS), Alcian blue (AB) at pH 2.5 and 1.0 and high-iron-diamine AB pH 2.5. Binding of lectins Con A, DBA, WGA, LTA, LFA, PNA and SBA; LFA, PNA and SBA with prior sialidase treatment; and paradoxical Con A were evaluated. The oesophagus lacked glands. The stomach was divided into a short cardias, a wide fundus and a brief pylorus. The surface muciparous cells secreted sulpho- and sialomucins with N-acetylgalactosamine (GalNAc) residues, N-acetyllactosamine and (beta1,4 N-acetylglucosamine)(n) chains. Towards the pylorus, N-acetylgalactosamine residues disappeared and acidity decreased. Cardiac glands, neck cells in the fundic glands, pyloric and duodenal Brunner's glands all shared neutral, stable class-III mucins, mainly with N-acetylgalactosamine sequences. The intestine was divided into a duodenum, a jejuno-ileum and a short rectum. The goblet cells produced sulpho- and sialomucins with sialylated N-acetylgalactosamine sequences, (beta1,4 N-acetylglucosamine)(n) and N-acetyllactosamine, whose sialylation increased towards the rectum. The main features of the mucins are probably associated with the requirements of fast absorption and food passage and in protection against mechanical and pathogenic injuries.
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PMID:Lectin histochemistry of gastrointestinal glycoconjugates in the greater horseshoe bat, Rhinolophus ferrumequinum (Schreber, 1774). 1757 Apr 76