A drug discovery program run by Neurolixis in collaboration with researchers at Jagiellonian University (Krakow, Poland) has identified the first selective serotonin 5 HT1A receptor 'biased agonists' targeting beta-arrestin activation. Serotonin (5-hydroxytryptamine, 5-HT) is a key brain neurotransmitter that acts by activating neuronal receptors such as 5-HT1A. Neurolixis has developed a platform of novel compounds, known as ‘biased agonists’ that preferentially target specific intracellular signaling cascades via 5-HT1A receptors. The new study, reported in the Journal of Medicinal Chemistry, describes novel biased agonists that very selectively and potently activate beta-arrestin, a signaling mechanism at 5-HT1A receptors that is different to that targeted by previous Neurolixis biased agonists that target ERK1/2 phosphorylation. Notably, the beta-arrestin biased agonists exhibited distinct effects in rodent behavioral tests, likely reflecting specific neuronal signaling properties. The discovery may to lead to a new generation of molecules that differentially modulate this important neuronal receptor.
Adrian Newman-Tancredi CEO of Neurolixis commented, “We are excited that our drug discovery program has generated innovative compounds that could be relevant for treatment of central nervous system disorders such as depression or chronic pain.”
See the full publication (open access):
Discovery of novel pERK1/2- or β-Arrestin-Preferring 5-HT1A Receptor Biased Agonists: Diversified Therapeutic-Like vs. Side Effects Profile.
J Med Chem. 2020 Sep 4. doi: 10.1021/acs.jmedchem.0c00814. PMID: 32883072