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

摘要: The α1-adrenoceptors (α1-ARs), in particular the α1A-AR subtype, are current therapeutic targets of choice for treatment urogenital conditions, such as benign prostatic hyperplasia (BPH). Due to similarity between transmembrane domains α1-AR subtypes, and serotonin receptor subtype 1A (5-HT1A-R), currently used subtype-selective drugs treat BPH display considerable off-target affinity 5-HT1A-R, leading side effects. We describe construction validation pharmacophores 5-HT1A-R agonists antagonists. Through structural diversity training sets their development, these define properties a compound needed bind 5-HT1A receptors. Using previously published virtual screening profiling, we have identified unique chemical compounds (hits) that fit requirements our target, α1A-AR, selectively over off-target, 5-HT1A-R. Selected hits been obtained affinities α1B-AR determined radioligand binding assays, using membrane preparations which contain human receptors expressed individually. Three tested demonstrate statistically significant selectivity All seven with two displaying K i values below 1 μM, further around 10 μM. insights knowledge gained through development new will greatly aid design synthesis derivatives lead compound, allow generation more efficacious selective ligands.