Abstract
Some 5-HT2B fluorescent probes were obtained by tagging 1-(2,5-dimethoxy-4-iodophenyl)-propan-2-amine (DOI) with a subset of fluorescent amines. Some of the resulting fluorescent ligands showed excellent affinity and selectivity profiles at the 5-HT2B receptors (e.g. 12b), while retain the agonistic functional behaviour of the model ligand (DOI). The study highlighted the most salient features of the structure-activity relationship in this series and these were substantiated by a molecular modelling study based on a receptor-driven docking model constructed on the basis of the crystal structure of the human 5-HT2B receptor. One of the fluorescent ligands developed in this work, compound 12i, specifically labelled CHO-K1 cells expressing 5-HT2B receptors and not parental CHO-K1 cells in a concentration-dependent manner. 12i enables imaging and quantification of specific 5-HT2B receptor labelling in live cells by automated fluorescence microscopy as well as quantification by measurements of fluorescence intensity using a fluorescence plate reader.
Highlights
The biogenic amine serotonin, 5-hydroxytryptamine (5-HT), is one of the most versatile chemical messengers in the central and peripheral nervous systems[1]
The 5-HT2 receptor family comprises three closely related receptor subtypes[8, 9], namely 5-HT2A, 5-HT2B, and 5-HT2C, that are the molecular targets of prominent drugs acting in different therapeutic areas1–4, 9–11. 5-HT2 receptor subtypes mediate many of the central and peripheral physiological functions of serotonin[1,2,3,4] and they couple preferentially to Gq/11 to increase the hydrolysis of inositol phosphates (IPs) and elevate cytosolic Ca2+
The 5-HT2B subtype remains one of the most attractive and enigmatic receptors amongst the 5-HT receptor superfamily[12, 13], with key functional, signalling, and regulatory aspects remaining ambiguous. The involvement of this receptor in the development of migraine[14], the modulation of the 5-HT transport system[15], and the rewarding and reinforcing effects of the widely abused drug ecstasy (3,4-methylenedioxy-N-methylamphetamine, MDMA) has been validated16. 5-HT2B receptor participate in other relevant processes, in the cardiovascular system where it regulates cardiac development and cardiomyocyte proliferation and survival17, 18. 5-HT2B activation has been associated with diverse pathologies[19, 20]
Summary
The biogenic amine serotonin, 5-hydroxytryptamine (5-HT), is one of the most versatile chemical messengers in the central and peripheral nervous systems[1]. 5-HT2 receptor subtypes mediate many of the central and peripheral physiological functions of serotonin[1,2,3,4] and they couple preferentially to Gq/11 to increase the hydrolysis of inositol phosphates (IPs) and elevate cytosolic Ca2+. This similar functional behaviour is supported by a high structural homology . The new ligands combine good fluorescence properties with satisfactory affinity and selectivity; these molecular probes can contribute to a better understanding of the physiological and pathological implications of 5-HT2B receptors
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