Journal Article

5-HT sub(1A) receptor pharmacophores to screen for off-target activity of alpha sub(1)-adrenoceptor antagonists

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

2013

Overview

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.

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