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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 cycl, In Vitro, Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

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 cycl, In Vitro, Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

A series of novel 1,2,4-pyridothiadiazine 1,1-dioxides (1), some of them being pyridyl analogues of the 1,2,4-benzothiadiazine 1,1-dioxide diazoxide (2), were synthesized and selected physicochemical data (pKa, log P′) were collected. By means of spectral (13C NMR, UV) and X-ray data, the most favourable position of the C=N double bond in the thiadiazine ring was discussed. It was concluded that like 1,2,4-benzothiadiazine 1,1-dioxides, 1,2,4-pyridothiadiazine 1,1-dioxides free of an alkyl substituent in the 2- and 4-positions, whatever the nitrogen atom position in the pyridine ring, show predominance of the tautomeric 4H-form. © 1995., SCOPUS: ar.j, info:eu-repo/semantics/published

A series of novel 1,2,4-pyridothiadiazine 1,1-dioxides (1), some of them being pyridyl analogues of the 1,2,4-benzothiadiazine 1,1-dioxide diazoxide (2), were synthesized and selected physicochemical data (pKa, log P′) were collected. By means of spectral (13C NMR, UV) and X-ray data, the most favourable position of the C=N double bond in the thiadiazine ring was discussed. It was concluded that like 1,2,4-benzothiadiazine 1,1-dioxides, 1,2,4-pyridothiadiazine 1,1-dioxides free of an alkyl substituent in the 2- and 4-positions, whatever the nitrogen atom position in the pyridine ring, show predominance of the tautomeric 4H-form. © 1995., SCOPUS: ar.j, info:eu-repo/semantics/published