Discovery of functionally selective 7,8,9,10-tetrahydro-7,10-ethano-1,2,4- triazolo[3,4-a]phthalazines as GABAA receptor agonists at the α3 subunit

Article abstract of DOI:10.1021/jm040883v

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 0.3 receptor subtype with 5-fold selectivity in binding affinity over α₁. 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 α₃ subtype over the α₁ subtype was 12-fold (for 57). Although most analogues showed no selectivity in terms of efficacy, some did show partial agonism at α₁ and antagonism at α₃ (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 α₃ subtype over the α₁ subtype. This was the first indication that selectivity in efficacy in the required direction could be achieved in this series.