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: Phthalazine; Alpha (finance); Structure–activity relationship

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 alpha(3) receptor subtype with 5-fold selectivity in binding affinity over alpha(1). This paper describes detailed investigation of substituents on this core structure at both 3- and 6-positions. Despite evaluating wide range groups, maximum that could be achieved terms alpha(1) was 12-fold (for 57). Although most analogues showed no efficacy, some did show agonism antagonism (e.g., 25 75). However, two tested (93 96), triazole 6-position, significantly higher efficacy subtype. first indication required direction series.