Details

Autor(en) / Beteiligte

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

Titel

5-HT^sub 1A^ receptor pharmacophores to screen for off-target activity of [alpha]^sub 1^-adrenoceptor antagonists

Ist Teil von

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

Ort / Verlag

Dordrecht: Springer Nature B.V

Erscheinungsjahr

2013

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• The [alpha]^sub 1^-adrenoceptors ([alpha]^sub 1^-ARs), in particular the [alpha]^sub 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 [alpha]^sub 1^-AR subtypes, and the serotonin receptor subtype 1A (5-HT^sub 1A^-R), currently used [alpha]^sub 1^-AR subtype-selective drugs to treat BPH display considerable off-target affinity for the 5-HT^sub 1A^-R, leading to side effects. We describe the construction and validation of pharmacophores for 5-HT^sub 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^sub 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 [alpha]^sub 1A^-AR, selectively over the off-target, the 5-HT^sub 1A^-R. Selected hits have been obtained and their affinities for [alpha]^sub 1A^-AR, [alpha]^sub 1B^-AR and 5-HT^sub 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 [alpha]^sub 1A^-AR over 5-HT^sub 1A^-R. All seven tested hits bind to [alpha]^sub 1A^-AR, with two compounds displaying K ^sub i^ values below 1 [mu]M, and a further two K ^sub i^ values of around 10 [mu]M. The insights and knowledge gained through the development of the new 5-HT^sub 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.[PUBLICATION ABSTRACT]