Biased receptor

Kenakin, T. P. (2011). Functional selectivity and biased receptor signaling. The Journal of Pharmacology and Experimental Therapeutics, 336, 296—302. 

Jonsson MK, Vos MA, Mirams GR, Duker G, Sartipy P, de Boer TP, van Veen TA (2012) Application of human stem cell-derived cardiomyocytes in safety pharmacology requires caution beyond hERG. J Mol Cell Cardiol 52(5) 998-1008 Kenakin T (2011) Functional selectivity and biased receptor signaling. J Pharmacol Exp Ther 336... 

Watson, C., Chen, G., Irving, P. E., Way, J., Chen, W.-J., and Kenakin, T. P. (2000). The use of stimulus-biased assay systems to detect agonist-specific receptor active states Implications for the trafficking of receptor stimulus by agonists. Mol. Pharmacol. 58 1230-1238. 

This term indicates a receptor ligand having different intrinsic activities at different transduction pathways coupled to a single receptor. To quote Urban et al. (2006 JPET, 104463 PiP) and Kenakin (2007 Trends Pharmacol Sci 28 359-361) the term biased agonism can be considered as a synonym of collateral efficacy, ... 

Brown, P. J., Smith-Oliver, T. A., Charifson, P. S., et al. (1997) Identification of peroxisome proliferator-activated receptor ligands from a biased chemical library. 

In my admittedly biased view, the most coherent approach is that of a profoundly disturbed stress system that under specific conditions paves the way to development of mood disorders. These stress-system alterations can be genetic or acquired through trauma in early life or even in utero. Consistent with this neuroendocrine hypothesis are findings that centrally released neuropeptides that drive the HPA system also have behavioral effects that are similar to affective symptoms. This view is further supported by the documented ability of various antidepressants to enhance corticosteroid receptor synthesis and efficacy. Moreover, the stress system, particularly the corticosteroids and their receptors, interferes with all of the neurotransmitter receptor systems, including intracellular signaling, that have been considered in the context of mood disorders. New drugs targeted directly to various elements of the stress system will constitute a major step forward. 

To validate the equilibrated receptor, its potency to predict free energies of binding (AGpiej) is examined. Therefore, classical QSAR methods such as cross-validation via leave-X%-out analyses and/or prediction of activity for an external set of compounds (test set) are accomplished. Since all QSAR models are typically constructed to predict properties of new or even virtual molecules, model validation with an external test set reflects reality best (unbiased or biased random selection of training set and test set ligands is supported by the software). 

---