Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 47 (14), 3642-57

Synthesis and Biological Evaluation of 3-heterocyclyl-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazines and Analogues as Subtype-Selective Inverse Agonists for the GABA(A)alpha5 Benzodiazepine Binding Site

Affiliations

Synthesis and Biological Evaluation of 3-heterocyclyl-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazines and Analogues as Subtype-Selective Inverse Agonists for the GABA(A)alpha5 Benzodiazepine Binding Site

Leslie J Street et al. J Med Chem.

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.

Similar articles

See all similar articles

Cited by 7 PubMed Central articles

See all "Cited by" articles

MeSH terms

Substances

LinkOut - more resources

Feedback