R. Carling, K. Moore, L. Street
Mar 2, 2004
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Influential Citations
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Quality indicators
Journal
Journal of Medicinal Chemistry
Abstract
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 (Ki: α2 = 1.7 nM, α3 = 0.71 nM, α5 = 0.33 nM, α1 = 2.7 nM). Furthermore, on evaluation in xenopus oocytes,22 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-subs...