ABSTRACT
The development of a series of GABA(A) alpha2/alpha3 subtype selective pyridazine based benzodiazepine site agonists as anxiolytic agents with reduced sedative/ataxic potential is described, including the discovery of 16, a remarkably alpha3-selective compound ideal for in vivo study. These ligands are antagonists at the alpha1 subtype, with good CNS penetration and receptor occupancy, and excellent oral bioavailability.
Subject(s)
Anti-Anxiety Agents/pharmacology , Anxiety/drug therapy , GABA Agonists/pharmacology , GABA-A Receptor Agonists , Pyridazines/pharmacology , Animals , Anti-Anxiety Agents/administration & dosage , Anti-Anxiety Agents/chemical synthesis , Binding Sites , GABA Agonists/administration & dosage , GABA Agonists/chemical synthesis , Humans , Ligands , Molecular Structure , Pyridazines/administration & dosage , Pyridazines/chemical synthesis , Rats , Recombinant Proteins/agonists , Stereoisomerism , Structure-Activity RelationshipABSTRACT
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
Imidazo[1,2-a]pyrimidines and imidazo[1,2-b][1,2,4]triazines are ligands for the benzodiazepine binding site of GABA(A) receptors that are functionally selective for the alpha2/alpha3 subtypes over the alpha1 subtype. SAR studies to optimise this functional selectivity, pharmacokinetic and behavioural data are described.
Subject(s)
Anxiety Disorders/drug therapy , GABA-A Receptor Agonists , Imidazoles/pharmacology , Protein Subunits/agonists , Triazines/pharmacology , Administration, Oral , Animals , Ataxia/drug therapy , Binding Sites , Biological Availability , Disease Models, Animal , Dogs , Female , GABA Agonists/pharmacokinetics , GABA Agonists/pharmacology , Imidazoles/pharmacokinetics , Male , Maze Learning/drug effects , Molecular Structure , Protein Subunits/metabolism , Rats , Rats, Sprague-Dawley , Receptors, GABA-A/metabolism , Saimiri , Structure-Activity Relationship , Triazines/pharmacokineticsABSTRACT
The GABA(A) receptor subtypes responsible for the anxiolytic effects of nonselective benzodiazepines (BZs) such as chlordiazepoxide (CDP) and diazepam remain controversial. Hence, molecular genetic data suggest that alpha2-rather than alpha3-containing GABA(A) receptors are responsible for the anxiolytic effects of diazepam, whereas the anxiogenic effects of an alpha3-selective inverse agonist suggest that an agonist selective for this subtype should be anxiolytic. We have extended this latter pharmacological approach to identify a compound, 4,2'-difluoro-5'-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-á]pyridin-3-yl]biphenyl-2-carbonitrile (TP003), that is an alpha3 subtype selective agonist that produced a robust anxiolytic-like effect in both rodent and non-human primate behavioral models of anxiety. Moreover, in mice containing a point mutation that renders alpha2-containing receptors BZ insensitive (alpha2H101R mice), TP003 as well as the nonselective agonist CDP retained efficacy in a stress-induced hyperthermia model. Together, these data show that potentiation of alpha3-containing GABA(A) receptors is sufficient to produce the anxiolytic effects of BZs and that alpha2 potentiation may not be necessary.
