3,4-Dihydronaphthalen-1(2H)-ones: novel ligands for the benzodiazepine site of alpha5-containing GABAA receptors

Helen J Szekeres; John R Atack; Mark S Chambers; Susan M Cook; Alison J Macaulay; Gopalan V Pillai; Angus M MacLeod

doi:10.1016/j.bmcl.2004.03.054

3,4-Dihydronaphthalen-1(2H)-ones: novel ligands for the benzodiazepine site of alpha5-containing GABAA receptors

Bioorg Med Chem Lett. 2004 Jun 7;14(11):2871-5. doi: 10.1016/j.bmcl.2004.03.054.

Authors

Helen J Szekeres¹, John R Atack, Mark S Chambers, Susan M Cook, Alison J Macaulay, Gopalan V Pillai, Angus M MacLeod

Affiliation

¹ Merck, Sharp & Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK.

PMID: 15125950
DOI: 10.1016/j.bmcl.2004.03.054

Abstract

A series of substituted 3,4-dihydronaphthalen-1(2H)-ones with high binding affinity for the benzodiazepine site of GABAA receptors containing the alpha5-subunit has been identified. These compounds have consistently higher binding affinity for the GABAA alpha5 receptor subtype over the other benzodiazepine-sensitive GABAA receptor subtypes (alpha1, alpha2 and alpha3). Compounds with a range of efficacies for the benzodiazepine site of alpha5-containing GABAA receptors were identified, including the alpha5 inverse agonist 3,3-dimethyl-8-methylthio-5-(pyridin-2-yl)-3,4-dihydronaphthalen-1(2H)-one 22 and the alpha5 agonist 8-ethylthio-3-methyl-5-(1-oxidopyridin-2-yl)-3,4-dihydronaphthalen-1(2H)-one 19.

MeSH terms

Allosteric Site
Benzodiazepines / antagonists & inhibitors
Binding Sites
GABA-A Receptor Agonists
GABA-A Receptor Antagonists
Humans
Ligands
Naphthalenes / chemical synthesis
Naphthalenes / pharmacology*
Protein Binding
Protein Subunits
Receptors, GABA-A / drug effects*
Structure-Activity Relationship

Substances

GABA-A Receptor Agonists
GABA-A Receptor Antagonists
Ligands
Naphthalenes
Protein Subunits
Receptors, GABA-A
Benzodiazepines