Novel 5-Hydroxytryptamine Receptor (5-HT1B) Antagonists Library designed to achieve subtype-selectivity
Posted Oct 07 2013 7:36am
5-HT 1Bserotonin receptors are involved in regulation of several physiological functions, behavior and psychiatric diseases including locomotor activity, vascular smooth muscle constriction, aggressive behavior, migraine, depression and anxiety states. Inactivation of 5-HT 1B receptors might affect attention and emotion and have positive effects on learning and memory processes. However, clinical application of 5-HT 1B receptor inhibitors can cause unexpected side effectsarising from interactions withother5-HT receptor subtypes. The lack of specific5-HT 1B antagonists ledOTAVAto design focused library containing compoundsspecifically targeted towards 5-HT 1B receptor in such a way to minimize cross-reactivity with 5-HT 2B receptor.
OTAVA focused library of5-HT 1B antagonists(1,836 compounds in total)has been designed using receptor-based virtual screening of pre-filtered compound collection docked into orthosteric and extended pockets of the5-HT 1B ligand binding site. The 5-HT 1Bsubtype-targetedantagonistshavebeenselected withinspection of active site critical structural determinants for ligand recognition, validation of reference set of 26 known 5-HT antagonists and exclusion of predicted 5-HT 2B binders from the final set of compounds by similarity analysis and docking score cut-off filtering.In order to increase the potential for blood-brain barrier penetration, the library falls into the following physicochemical property ranges: MolWeight < 450, number of H donors ≤ 3, number of H acceptors ≤ 9, CLogP 2-5, LogD 2-5 and PSA < 90.
We hope that OTAVA’sfocused library of5-HT 1B antagonists willhelp drug discovery scientists to develop treatments based on the inhibition of this subtype of serotonin receptors.