Synthesis and biological evaluation of 3-heterocyclyl-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazine s and analogues as subtype-selective inverse agonists for the GABA(A)alpha5 benzodiazepine binding site.

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Street LJ, Sternfeld F, Jelley RA, Reeve AJ, Carling RW, Moore KW, McKernan RM, Sohal B, Cook S, Pike A, Dawson GR, Bromidge FA, Wafford KA, Seabrook GR, Thompson SA, Marshall G, Pillai GV, Castro JL, Atack JR, MacLeod AM

J Med Chem. 2004 Jul 1;47(14):3642-57.

PubMed ID

15214791 [ View in PubMed

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Abstract

The identification of a novel series of 7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazines as GABA(A)alpha5 inverse agonists, which have both binding and functional (efficacy) selectivity for the benzodiazepine binding site of alpha5- over alpha1-, alpha2-, and alpha3-containing GABA(A) receptor subtypes, is described. Binding selectivity was determined to a large part by the degree of planarity of the fused ring system whereas functional selectivity was dependent on the nature of the heterocycle at the 3-position of the triazolopyridazine ring. 3-Furan and 5-methylisoxazole were shown to be optimal for GABA(A)alpha5 functional selectvity. 3-(5-Methylisoxazol-3-yl)-6-(2-pyridyl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine (43) was identified as a full inverse agonist at the GABA(A)alpha5 subtype with functional selectivity over the other GABA(A) receptor subtypes and good oral bioavailability.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Zolpidem	Gamma-aminobutyric acid receptor subunit alpha-1	Ki (nM)	52.1	N/A	N/A	Details
Zolpidem	Gamma-aminobutyric acid receptor subunit gamma-2	Ki (nM)	>10000	N/A	N/A	Details
Zolpidem	Gamma-aminobutyric acid receptor subunit gamma-2	Ki (nM)	255.1	N/A	N/A	Details
Zolpidem	Gamma-aminobutyric acid receptor subunit gamma-2	Ki (nM)	608.5	N/A	N/A	Details