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

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Abstract

The α1-adrenoceptors (α1-ARs), in particular the α1A-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 α1-AR subtypes, and the serotonin receptor subtype 1A (5-HT1A-R), currently used α1-AR subtype-selective drugs to treat BPH display considerable off-target affinity for the 5-HT1A-R, leading to side effects. We describe the construction and validation of pharmacophores for 5-HT1A-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-HT1A 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 α1A-AR, selectively over the off-target, the 5-HT1A-R. Selected hits have been obtained and their affinities for α1A-AR, α1B-AR and 5-HT1A-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 α1A-AR over 5-HT1A-R. All seven tested hits bind to α1A-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-HT1A-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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Notes

  1. Numbers indicate the Ballesteros-Weinstein numbering scheme where the first digit represents the transmembrane helix (TM) number followed by the position relative to the most conserved residue in each TM, assigned number 50. Numbers decrease towards the N-terminus.

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Acknowledgments

The authors wish to acknowledge the help of Dr Luke Hunter, School of Chemistry, University of New South Wales, in determining the purity and identity of the test compounds, using the Analytical Centre Facilities. J. Chen wishes to acknowledge financial support through a China Scholarship Council scholarship.

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  1. Department of Pharmacology, School of Medical Sciences, The University of New South Wales, UNSW Sydney, NSW, 2052, Australia

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

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  1. Tony Ngo
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Correspondence to Renate Griffith.

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Tony Ngo and Timothy J. Nicholas have contributed equally.

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Ngo, T., Nicholas, T.J., Chen, J. et al. 5-HT1A receptor pharmacophores to screen for off-target activity of α1-adrenoceptor antagonists. J Comput Aided Mol Des 27, 305–319 (2013). https://doi.org/10.1007/s10822-013-9647-5

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