Linked Life Data

9685234

Source:http://linkedlifedata.com/resource/pubmed/id/9685234

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
16
pubmed:dateCreated
1998-8-17
pubmed:abstractText
A series of 4H-1,2,4-pyridothiadiazine 1,1-dioxides and 2, 3-dihydro-4H-1,2,4-pyridothiadiazine 1,1-dioxides bearing various alkyl and aryl substituents on the 2-, 3-, and 4-positions was synthesized and tested as possible positive allosteric modulators of the (R/S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors. Many compounds were found to be more potent than the reference compounds diazoxide and aniracetam as potentiators of the AMPA current in rat cortex mRNA-injected Xenopus oocytes. The most active compound, 4-ethyl-2,3-dihydro-4H-pyrido[3,2-e]-1,2, 4-thiadiazine 1,1-dioxide (31b), revealed an in vitro activity on Xenopus oocytes not far from that of cyclothiazide, the most potent allosteric modulator of AMPA receptors reported to date. Moreover, 31b, but not cyclothiazide, was found to potentiate the duration and the amplitude of the excitatory postsynaptic field potentials induced by electric stimulation in rat hippocampal slices. Such an effect could indicate, for 31b, but not for cyclothiazide, a possible interaction with postsynaptic AMPA receptor binding sites located on hippocampal CA1 neurons. Structure-activity relationships indicated that the structural requirements responsible for a biological activity on AMPA receptors are different from those responsible for an inhibitory activity on the insulin releasing process (putative ATP-sensitive K+-channel openers). For instance, 31b and other related dihydropyridothiadiazines were found to be ineffective as inhibitors of insulin release from rat pancreatic B-cells, in contrast to diazoxide and known pyridothiadiazines reported as ATP-sensitive K+-channel openers. Conversely, the pyridothiadiazines active on B-cells were found to be ineffective as potentiators of the AMPA currents in Xenopus oocytes. Thus, 31b appeared to be more specific than diazoxide as an AMPA receptor modulator. This compound may be considered as a new pharmacological tool, different from diazoxide and cyclothiazide, for studying AMPA receptors. Moreover, 31b can also constitute a new therapeutic agent for the treatment of cognitive disorders.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
30
pubmed:volume
41
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2946-59
pubmed:dateRevised
2011-11-17
pubmed:meshHeading
pubmed-meshheading:9685234-Adenosine Triphosphate, pubmed-meshheading:9685234-Allosteric Regulation, pubmed-meshheading:9685234-Animals, pubmed-meshheading:9685234-Benzothiadiazines, pubmed-meshheading:9685234-Cerebral Cortex, pubmed-meshheading:9685234-Cyclic S-Oxides, pubmed-meshheading:9685234-Diazoxide, pubmed-meshheading:9685234-Drug Design, pubmed-meshheading:9685234-Excitatory Postsynaptic Potentials, pubmed-meshheading:9685234-Hippocampus, pubmed-meshheading:9685234-Insulin, pubmed-meshheading:9685234-Insulin Antagonists, pubmed-meshheading:9685234-Islets of Langerhans, pubmed-meshheading:9685234-Male, pubmed-meshheading:9685234-Mice, pubmed-meshheading:9685234-Mice, Inbred DBA, pubmed-meshheading:9685234-Oocytes, pubmed-meshheading:9685234-Potassium Channels, pubmed-meshheading:9685234-RNA, Messenger, pubmed-meshheading:9685234-Rats, pubmed-meshheading:9685234-Rats, Wistar, pubmed-meshheading:9685234-Receptors, AMPA, pubmed-meshheading:9685234-Solubility, pubmed-meshheading:9685234-Stereoisomerism, pubmed-meshheading:9685234-Structure-Activity Relationship, pubmed-meshheading:9685234-Thiadiazines, pubmed-meshheading:9685234-Xenopus laevis
pubmed:year
1998
pubmed:articleTitle
4H-1,2,4-Pyridothiadiazine 1,1-dioxides and 2,3-dihydro-4H-1,2, 4-pyridothiadiazine 1,1-dioxides chemically related to diazoxide and cyclothiazide as powerful positive allosteric modulators of (R/S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid receptors: design, synthesis, pharmacology, and structure-activity relationships.
pubmed:affiliation
Laboratoire de Chimie Pharmaceutique, Université de Liège, 3, rue Fusch, B-4000 Liège, Belgium, Laboratoire de Pharmacodynamie et de Thérapeutique, Université Libre de Bruxelles, 808, route de Lennik, B-1070 Bruxelles, Belgium.
pubmed:publicationType
Journal Article, In Vitro, Research Support, Non-U.S. Gov't