ABSTRACT
The identification of a series of imidazo[1,2-b][1,2,4]triazines with high affinity and functional selectivity for the GABA(A) alpha3-containing receptor subtype is described, leading to the identification of a clinical candidate, 11. Compound 11 shows good bioavailability and half-life in preclinical species, and it is a nonsedating anxiolytic in both rat and squirrel monkey behavioral models.
Subject(s)
Anti-Anxiety Agents/chemical synthesis , GABA-A Receptor Agonists , Imidazoles/chemical synthesis , Triazines/chemical synthesis , Animals , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacology , Biological Availability , Half-Life , Humans , Imidazoles/chemistry , Imidazoles/pharmacology , Patch-Clamp Techniques , Radioligand Assay , Rats , Receptors, GABA-A/physiology , Saimiri , Structure-Activity Relationship , Triazines/chemistry , Triazines/pharmacologyABSTRACT
We have previously identified the 7,8,9,10-tetrahydro-7,10-ethano-1,2,4-triazolo[3,4-a]phthalazine (1) as a potent partial agonist for the alpha(3) receptor subtype with 5-fold selectivity in binding affinity over alpha(1). This paper describes a detailed investigation of the substituents on this core structure at both the 3- and 6-positions. Despite evaluating a wide range of groups, the maximum selectivity that could be achieved in terms of affinity for the alpha(3) subtype over the alpha(1) subtype was 12-fold (for 57). Although most analogues showed no selectivity in terms of efficacy, some did show partial agonism at alpha(1) and antagonism at alpha(3) (e.g., 25 and 75). However, two analogues tested (93 and 96), both with triazole substituents in the 6-position, showed significantly higher efficacy for the alpha(3) subtype over the alpha(1) subtype. This was the first indication that selectivity in efficacy in the required direction could be achieved in this series.
Subject(s)
GABA-A Receptor Agonists , Phthalazines/chemical synthesis , Triazoles/chemical synthesis , Animals , Binding Sites , Cell Line , Female , Humans , Models, Molecular , Oocytes/drug effects , Oocytes/physiology , Patch-Clamp Techniques , Phthalazines/chemistry , Phthalazines/pharmacology , Protein Subunits/agonists , Protein Subunits/physiology , Radioligand Assay , Receptors, GABA-A/physiology , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/pharmacology , Xenopus laevisABSTRACT
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
A novel series of 3-heteroaryl-5,6-bis(aryl)-1-methyl-2-pyridones were developed with high affinity for the benzodiazepine (BZ) binding site of human gamma-aminobutyric acid (GABA(A)) receptor ion channels, low binding selectivity for alpha 2- and/or alpha 3- over alpha 1-containing GABA(A) receptor subtypes and high binding selectivity over alpha 5 subtypes. High affinity appeared to be associated with a coplanar conformation of the pyridone and sulfur-containing 3-heteroaryl rings resulting from an attractive S.O intramolecular interaction. Functional selectivity (i.e., selective efficacy) for alpha 2 and/or alpha 3 GABA(A) receptor subtypes over alpha1 was observed in several of these compounds in electrophysiological assays. Furthermore, an alpha 3 subtype selective inverse agonist was proconvulsant and anxiogenic in rodents while an alpha 2/alpha 3 subtype selective partial agonist was anticonvulsant and anxiolytic, supporting the hypothesis that subtype selective BZ site agonists may provide new anxiolytic therapies.
Subject(s)
Pyridones/chemical synthesis , Receptors, GABA-A/drug effects , Animals , Anti-Anxiety Agents/chemical synthesis , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacokinetics , Anti-Anxiety Agents/pharmacology , Anticonvulsants/chemical synthesis , Anticonvulsants/chemistry , Anticonvulsants/pharmacokinetics , Anticonvulsants/pharmacology , Biological Availability , Brain/metabolism , Cell Line , Convulsants/chemical synthesis , Convulsants/chemistry , Convulsants/pharmacokinetics , Convulsants/pharmacology , Crystallography, X-Ray , Epilepsy/drug therapy , GABA Agonists/chemical synthesis , GABA Agonists/chemistry , GABA Agonists/pharmacokinetics , GABA Agonists/pharmacology , Humans , In Vitro Techniques , Ligands , Maze Learning/drug effects , Mice , Oocytes , Patch-Clamp Techniques , Protein Subunits , Pyridones/chemistry , Pyridones/pharmacokinetics , Pyridones/pharmacology , Radioligand Assay , Rats , Receptors, GABA-A/metabolism , Receptors, GABA-A/physiology , Structure-Activity Relationship , XenopusABSTRACT
Nonselective inverse agonists at the benzodiazepine binding site on the GABA-A chloride ion channel enhance cognitive performance in animals but cannot be used in the treatment of cognitive disorders because of anxiogenic and convulsant side effects. We have identified a novel series of GABA-A alpha5 receptor ligands during our search for alpha5 receptor inverse agonists as potential cognition enhancers. In particular, 6,6-dimethyl-3-(2-hydroxyethyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one (26) has been identified as a functionally selective GABA-A alpha5 inverse agonist.
