Details

Autor(en) / Beteiligte

• Ngo, Tony
• Nicholas, Timothy J.
• Chen, Junli
• Finch, Angela M.
• Griffith, Renate

Titel

5-HT1A receptor pharmacophores to screen for off-target activity of α1-adrenoceptor antagonists

Ist Teil von

• Journal of computer-aided molecular design, 2013-04, Vol.27 (4), p.305-319

Ort / Verlag

Dordrecht: Springer Netherlands

Erscheinungsjahr

2013

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• The α 1 -adrenoceptors (α 1 -ARs), in particular the α 1A -AR subtype, are current therapeutic targets of choice for the treatment of urogenital conditions, such as benign prostatic hyperplasia (BPH). Due to the similarity between the transmembrane domains of the α 1 -AR subtypes, and the serotonin receptor subtype 1A (5-HT 1A -R), currently used α 1 -AR subtype-selective drugs to treat BPH display considerable off-target affinity for the 5-HT 1A -R, leading to side effects. We describe the construction and validation of pharmacophores for 5-HT 1A -R agonists and antagonists. Through the structural diversity of the training sets used in their development, these pharmacophores define the properties of a compound needed to bind to 5-HT 1A receptors. Using these and previously published pharmacophores in virtual screening and profiling, we have identified unique chemical compounds (hits) that fit the requirements to bind to our target, the α 1A -AR, selectively over the off-target, the 5-HT 1A -R. Selected hits have been obtained and their affinities for α 1A -AR, α 1B -AR and 5-HT 1A -R determined in radioligand binding assays, using membrane preparations which contain human receptors expressed individually. Three of the tested hits demonstrate statistically significant selectivity for α 1A -AR over 5-HT 1A -R. All seven tested hits bind to α 1A -AR, with two compounds displaying K i values below 1 μM, and a further two K i values of around 10 μM. The insights and knowledge gained through the development of the new 5-HT 1A -R pharmacophores will greatly aid in the design and synthesis of derivatives of our lead compound, and allow the generation of more efficacious and selective ligands.