SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Explore the source record for details and available documents.
7-Chloro-3-pyridyl(alkyl)amino-4H-1,2,4-benzothiadiazine 1,1-dioxides and 3-alkylamino-7-chloro-4H-1,2,4-benzothiadiazine 1,1-dioxides containing one or more heteroatoms on the side chain in the 3 position have been synthesized in an attempt to discover new potent KATP-channel openers. The compounds were tested as putative pancreatic B-cells KATP channel openers by measuring their inhibitory activity on the insulin releasing process. The influence on the biological activity of the nature of the side chain in the 3 position is discussed.
The direct analytical and semipreparative high-performance liquid chromatographic (HPLC) resolution of the enantiomers of IDRA 21 [1,7-chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine S,S-dioxide] is reported. (+/-)-IDRA 21 administered orally to rats subjected to a water maze cognition test elicited a performance enhancing effect. Between the two enantiomers, (+)-IDRA 21 was identified as being pharmacologically active in the water maze performance test, whereas (-)-IDRA 21 was completely devoid of activity when given in doses comparable to those of the dextrorotatory (+)-enantiomer. The design and preparation of a new chiral stationary phase (CSP) employed for the liquid chromatographic resolution of the enantiomers of racemic IDRA 21 is presented. This brush-type CSP, which has not been described before, is a "mixed" (pi-donor pi-acceptor) type and is derived from (R)-N-(3,5-dinitrobenzoyl) allylglycine 2,6-dimethylanilide. It is easily prepared and possesses a relatively broad scope of applicability, as determined by its ability to resolve the enantiomers of both pi-acidic and pi-basic compounds.
A series of 2-substituted methyl 2,3-dihydroimidazo[1, 2-c]quinazolin-5(6H)-ones (4), 3-substituted methyl 2, 3-dihydroimidazo[1,2-c]quinazolin-5(6H)-ones (5), 3-substituted methyl 2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-5-ones (15a,b), 3-substituted methyl 2,3-dihydroimidazo[2,1-b]quinazolin-5(1H)-ones (16a,b), 3-substituted methyl 2,3-dihydro-1H-imidazo[1,2-b][1,2, 4]benzothiadiazine 5,5-dioxides (33a,b), 2-substituted methyl imidazo[1,2-c]quinazolin-5(6H)-ones (42-45a,b), 3-substituted methyl imidazo[1,2-c]quinazolin-5(6H)-ones (50-53a,b), 3-substituted methyl 5H-thiazolo[2,3-b]quinazolin-5-ones (55-56a,b), and 3-substituted methyl 5-(methylthio)-2,3-dihydroimidazo[1,2-c]quinazoline (57) were synthesized as compound 1conformational rigid congeners for pharmacological evaluation as potential alpha1-adrenoceptor antagonists. Compounds 4, 5, 33a,b, 44a,b, 45a,b, 52a,b, 53a,b, and 57 were found to possess high affinity for the alpha1-adrenoceptor. Compounds 5 and 57 were the most highly selective and potent alpha1 antagonists with Ki = 0.21 +/- 0.02 and 0.90 +/- 0.08 nM, respectively. The S-enantiomers of these two compounds (Ki = 0.13 +/- 0.01 nM for (S)-(-)-5; Ki = 1.0 +/- 0.2 nM for (S)-(+)-57) were 144-200-fold more potent than the R-enantiomers (Ki = 26 +/- 8 nM for (R)-(+)-5; Ki = 144 +/- 23 nM for (R)-(-)-57). Compound 4 showed 8-fold higher affinity to alpha1A-AR better than alpha1B-AR. These compounds possessed weak to no activity against the 5-HT1A receptor.
A series of dialkylamino, pyrrolidyl and morpholyl-alkyl-derivatives of 3-amino-1,2,4-benzothiadiazine-1,1-dioxide, 7- or 5,7-halogen substituted in the benzenoid moiety, was prepared and their cardiovascular activity studied. Most of the substances in question were capable of inducing a significant decrease in mean arterial blood pressure; some of them tended to increase pulse pressure or to cause bradycardia, an effect which was noted particularly in the case of compound 10 which reduced heart-rate by 85%. The structure/activity relationship of these substances, of the 6- and 6,7-halogen substituted isomers and of their corresponding non-substituted progenitors is examined.
7-Chloro-3-Methyl-3-4-Dihydro-2H-1,2,4 Benzothiadiazine S,S Dioxide (IDRA 21), which attenuates the rapid autodesensitization of DL-alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid (AMPA)-selective glutamate receptors and increases excitatory synaptic strength, improves cognition (learning and memory), as revealed by its ability to improve performance in water maze and passive avoidance tests in rats. Normal rats trained to (15-20 sec) reach the exit platform rapidly in a water maze that included four incorrect choices were given oral IDRA 21 (4-120 mumol/kg) or vehicle and then exposed to a delayed retention trial in a maze that included seven incorrect choices. In this retention trial, the IDRA 21-treated rats performed considerably better than those that received the vehicle. Moreover, oral IDRA 21 (ED50 = 7.6 microM) attenuated the performance impairment induced by the AMPA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo (F) quinoxaline in the water maze test. In this test and in a passive avoidance test, the performance impairment elicited by alprazolam, a full allosteric modulator at gamma-aminobutyric acid-A receptors, or by scopolamine, a competitive muscarinic receptor antagonist, was also reduced by oral administration of IDRA 21 (ED50 = 13 and 108 mumol/kg, against alprazolam and scopolamine, respectively); in all these tests, IDRA 21 was 20- to 30-fold more potent than aniracetam. Because IDRA 21 is a racemic molecule; the two stereoisomers were isolated and studied behaviorally. Only the (+) form was found to be behaviorally active. These results indicate that IDRA 21 given orally to rats presumably crosses the blood-brain barrier and acts stereoselectively on specific receptors that were operative during this behavioral procedure. Because the activity of IDRA 21 on rat cognition tests appears to be related to its ability to potentiate AMPA-activated currents, one can suggest that IDRA 21 improves cognition by acting on a stereoselective site of AMPA receptor that is operative in attenuating the rapid autodesensitization of these receptors.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.