Discovery of functionally selective 7,8,9,10-tetrahydro-7,10-ethano-1,2,4-triazolo[3,4-a]phthalazines as GABA A receptor agonists at the alpha3 subunit.

doi:10.1021/JM040883V

Paper

Discovery of functionally selective 7,8,9,10-tetrahydro-7,10-ethano-1,2,4-triazolo[3,4-a]phthalazines as GABA A receptor agonists at the alpha3 subunit.

Published Feb 4, 2005 · M. G. Russell, R. Carling, J. Atack

Journal of medicinal chemistry

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48

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Abstract

We have previously identified the 7,8,9,10-tetrahydro-7,10-ethano-1,2,4-triazolo[3,4-a]phthalazine (1) as a potent partial agonist for the alpha(3) receptor subtype with 5-fold selectivity in binding affinity over alpha(1). This paper describes a detailed investigation of the substituents on this core structure at both the 3- and 6-positions. Despite evaluating a wide range of groups, the maximum selectivity that could be achieved in terms of affinity for the alpha(3) subtype over the alpha(1) subtype was 12-fold (for 57). Although most analogues showed no selectivity in terms of efficacy, some did show partial agonism at alpha(1) and antagonism at alpha(3) (e.g., 25 and 75). However, two analogues tested (93 and 96), both with triazole substituents in the 6-position, showed significantly higher efficacy for the alpha(3) subtype over the alpha(1) subtype. This was the first indication that selectivity in efficacy in the required direction could be achieved in this series.

In Vitro Study

Study Snapshot

This study identifies functionally selective 7,8,9,10-tetrahydro-7,8,9,10-tetrahydro-1,2,4-triazolo[3,4-a]phthalazines as GABA A receptor agonists at the alpha3 subunit, with maximum selectivity

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Discovery of functionally selective 7,8,9,10-tetrahydro-7,10-ethano-1,2,4-triazolo[3,4-a]phthalazines as GABA A receptor agonists at the alpha3 subunit.

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References

Citations

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New triazoloquinoxaline-based derivatives show promising VEGFR-2 inhibitory activity and cytotoxic activity against cancer cells, with potential for anticancer treatment.

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This study demonstrates a facile method for preparing biologically relevant indazolophthalazinones, offering potential for synthetic transformations into bioactive scaffolds.

Ruthenium Catalyzed C-H Acylmethylation of N-Arylphthalazine-1,4-diones with α-Carbonyl Sulfoxonium Ylides: Highway to Diversely functionalized Phthalazino-fused Cinnolines.

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