eISSN: 2720-5371
ISSN: 1230-2813
Advances in Psychiatry and Neurology/Postępy Psychiatrii i Neurologii
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3/2017
vol. 26
 
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abstract:
Review paper

Functional selectivity – chance for better and safer drugs?

Joanna Śniecikowska
,
Monika Głuch-Lutwin
,
Adam Bucki
,
Paweł Mierzejewski
,
Marcin Kołaczkowski

Adv Psychiatry Neurol 2017; 26 (3): 165-178
Online publish date: 2017/09/30
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Purpose: The article reviews the current state of knowledge about functional selectivity (biased agonism) at G protein-coupled receptors (GPCRs), with a particular focus on serotonin 5-HT1A receptors.

Views: Recently, functional selectivity has been one of the fastest growing topics in GPCRs pharmacology. Research on this phenomenon allowed identification of signal transduction pathways which can be preferentially targeted to achieve improved therapeutic effects or, conversely, which are associated with adverse effects. Oliceridine, a phase III clinical candidate for treatment of pain, is an example of a functionally selective ligand of µ-opioid receptors that preferentially activates signal transduction via G proteins rather than β-arrestin. Biased agonism, or the ability to preferentially activate specific signalling pathways, has been identified for many therapeutically important GPCRs, such as µ-opioid receptors, α1- and β2-adrenoceptors, dopamine D2L and D1 receptors, angiotensin 1A receptor, as well as 5-HT2 and 5-HT1A serotonin receptors. The recently discovered compounds F15599 and F13714 have been identified as functionally and regionally selective ligands of 5-HT1A receptors. These compounds constitute a new generation of pharmacological tools with high therapeutic potential, which is currently being investigated for the treatment of disorders including Parkinson’s disease, depression and Rett syndrome.

Conclusions: Functional selectivity (biased agonism) enables separation of the therapeutic effect from the adverse effects, so far considered to be intrinsically linked to the mechanism of action, by preferentially targeting signal transduction pathways associated with beneficial effects. It may therefore offer new opportunities for improved development of more effective and safer drugs.
keywords:

functional selectivity, biased agonism, 5-HT1A receptor, F15599, F13714

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