Discovery of Functionally Selective 7,8,9,10-Tetrahydro-7,10-ethano-1,2,4-triazolo[3,4-a]phthalazines as GABAAReceptor Agonists at the α3Subunit

• DOI: 10.1021/jm040883v
• Publication Date: 2005-03-03T05:24:35Z
• Authors: Michael G. N. Rus...; Robert W. Carling; John R. Atack; Frances A. Bromidge; Susan M. Cook; Peter Hunt; Catherine Isted; Matt Lucas; Ruth M. McKernan; Andrew Mitchinson; Kevin W. Moore; Robert Narquizian; Alison J. Macaulay; David Thomas; Sally-Anne Thompson; Keith A. Wafford; José L. Castro
• Keywords: Models, Molecular; Binding Sites; Patch-Clamp Techniques; Triazoles; Receptors, GABA-A; 01 natural sciences; Cell Line; 0104 chemical sciences; Protein Subunits; Radioligand Assay; Structure-Activity Relationship; Xenopus laevis; Oocytes; Animals; Humans; Phthalazines; Female; GABA-A Receptor Agonists

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.