Serotonin Receptor (5HT2B) and ergotamine

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Serotonin receptors, specifically the 5-HT2B subtype, form a complex with ergotamine, represented here by lines. A recently discovered 5-HT6 receptor antagonist boasts high stability and strong binding affinity for the 5-HT6 receptor, without significant pharmacokinetic complications. Structure-Activity relationship studies have identified five key features of its pharmacophore that produce robust interactions with the receptor. The molecular components of this compound consist of a benzimidazole-based central aromatic ring (AR) scaffold, which is linked to a positive ionizable (PI) group via an ethyl chain, as well as a NHSO2 sulfonamide group attached at C6 of benzimidazole, acting as a hydrogen bond acceptor (HBA). Additionally, the compound features a 5-chloro-2-naphthyl group anchored to the HBA site, serving as its terminal hydrophobic region (HYD), and a chlorine atom bound to C5 of the 5-chloro-3-naphthyl group within HYD. The current model highlights several crucial interactions between these molecular components.