66978-73-2Relevant articles and documents
3-Phenyl-6-(2-pyridyl)methyloxy-1,2,4-triazolo[3,4-a]phthalazines and Analogues: High-Affinity γ-Aminobutyric Acid-A Benzodiazepine Receptor Ligands with α2, α3, and α5-Subtype Binding Selectivity over α1
Carling, Robert W.,Moore, Kevin W.,Street, Leslie J.,Wild, Deborah,Isted, Catherine,Leeson, Paul D.,Thomas, Steven,O'Connor, Desmond,McKernan, Ruth M.,Quirk, Katherine,Cook, Susan M.,Atack, John R.,Wafford, Keith A.,Thompson, Sally A.,Dawson, Gerard R.,Ferris, Pushpinder,Castro, José L.
, p. 1807 - 1822 (2007/10/03)
Studies with our screening lead 5 and the literature compound 6 led to the identification of 6-benzyloxy-3-(4-methoxy)phenyl-1,2,4-triazolo[3,4-a]phthalazine 8 as a ligand with binding selectivity for the γ-aminobutyric acid-A (GABA-A) α3- and α5-containing receptor subtypes over the GABA-A α1 subtype (Ki: α2 = 850 nM, α3 = 170 nM, α5 = 72 nM, α1 = 1400 nM). Early optimization studies identified the close analogue 10 (Ki: α2 = 16 nM, α3 = 41 nM, α5 = 38 nM, α1 = 280 nM) as a suitable lead for further study. High-affinity ligands were identified by replacing the 6-benzyloxy group of compound 10 with 2-pyridylmethoxy (compound 29), but binding selectivity was not enhanced (K i: α2 = 1.7 nM, α3 = 0.71 nM, α5 = 0.33 nM, α1 = 2.7 nM). Furthermore, on evaluation in xenopus oocytes, 29 was discovered to be a weak to moderate inverse agonist at all four receptor subtypes α1, -7%; α2, -5%; α3, -16%; α5, -5%). Replacement of the 3-phenyl group of 29 with alternatives led to reduced affinity, and smaller 3-substituents led to reduced efficacy. Methyl substitution of the benzo-fused ring of 29 at the 7-, 8-, and 10-positions resulted in increased efficacy although selectivity was abolished. Increased efficacy and retention of selectivity for α3 over α1 was achieved with the 7,8,9,10-tetrahydro-(7,10-ethano)-phthalazine 62. Compound 62 is currently one of the most binding selective GABA-A α3-benzodiazepine-site partial agonists known, and although its selectivity is limited, its good pharmacokinetic profile in the rat (33% oral bioavailability after a 3 mg/kg dose, reaching a peak plasma concentration of 179 ng/mL; half-life of 1 h) made it a useful pharmacological tool to explore the effect of a GABA-A α2/α3 agonist in vivo.
