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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Russell MG, Carling RW, Atack JR, Bromidge FA, Cook SM, Hunt P, Isted C, Lucas M, McKernan RM, Mitchinson A, Moore KW, Narquizian R, Macaulay AJ, Thomas D, Thompson SA, Wafford KA, Castro JL
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.
J Med Chem. 2005 Mar 10;48(5):1367-83.
- PubMed ID
- 15743180 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Zolpidem Gamma-aminobutyric acid receptor subunit alpha-1 Ki (nM) 27 N/A N/A Details Zolpidem Gamma-aminobutyric acid receptor subunit gamma-2 Ki (nM) 103 N/A N/A Details Zolpidem Gamma-aminobutyric acid receptor subunit gamma-2 Ki (nM) 246 N/A N/A Details Zolpidem Gamma-aminobutyric acid receptor subunit gamma-2 Ki (nM) >3333 N/A N/A Details