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.
Subject(s)
GABA-A Receptor Agonists , Isoxazoles/chemical synthesis , Phthalazines/chemical synthesis , Triazoles/chemical synthesis , Administration, Oral , Animals , Binding Sites , Biological Availability , Cell Line , Female , Humans , Isoxazoles/chemistry , Isoxazoles/pharmacology , Male , Maze Learning/drug effects , Oocytes/drug effects , Oocytes/physiology , Patch-Clamp Techniques , Phthalazines/chemistry , Phthalazines/pharmacokinetics , Phthalazines/pharmacology , Protein Subunits/agonists , Radioligand Assay , Rats , Structure-Activity Relationship , Triazoles/pharmacokinetics , Triazoles/pharmacology , Xenopus laevisABSTRACT
Nonselective inverse agonists at the gamma-aminobutyric acid(A) (GABA-A) benzodiazepine binding site have cognition-enhancing effects in animals but are anxiogenic and can precipitate convulsions. Herein, we describe novel GABA-A alpha5 subtype inverse agonists leading to the identification of 16 as an orally active, functionally selective compound that enhances cognition in animals without anxiogenic or convulsant effects. Compounds of this type may be useful in the symptomatic treatment of memory impairment associated with Alzheimer's disease and related dementias.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , GABA-A Receptor Agonists , Nootropic Agents/chemical synthesis , Phthalazines/chemical synthesis , Triazoles/chemical synthesis , Animals , Binding, Competitive , Biological Availability , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Convulsants/chemical synthesis , Convulsants/chemistry , Convulsants/pharmacology , Dogs , Humans , Macaca mulatta , Mice , Nootropic Agents/chemistry , Nootropic Agents/pharmacology , Oocytes/metabolism , Patch-Clamp Techniques , Phthalazines/chemistry , Phthalazines/pharmacology , Radioligand Assay , Rats , Receptors, GABA-A/physiology , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/pharmacology , Xenopus laevisABSTRACT
A series of tricyclic pyridones has been evaluated as benzodiazepine site ligands with functional selectivity for the alpha(3) over the alpha(1) containing subtype of the human GABA(A) receptor ion channel. This investigation led to the identification of a high affinity, functionally selective, orally bioavailable benzodiazepine site ligand that demonstrated activity in rodent anxiolysis models and reduced sedation relative to diazepam.
