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.
Subject(s)
Benzene Derivatives/chemistry , Fluorescent Dyes/chemistry , Propylamines/chemistry , Receptor, Serotonin, 5-HT2B/chemistry , Animals , Benzene Derivatives/chemical synthesis , CHO Cells , Cricetulus , Fluorescent Dyes/chemical synthesis , Humans , Ligands , Microscopy, Fluorescence/methods , Models, Molecular , Molecular Docking Simulation , Propylamines/chemical synthesis , Receptor, Serotonin, 5-HT2B/metabolism , Serotonin 5-HT2 Receptor Agonists/chemistry , Structure-Activity RelationshipABSTRACT
A practical, integrated and versatile U-4CR-based assembly of 1,4-benzodiazepin-2-ones exhibiting functionally, skeletally, and stereochemically diverse substitution patterns is described. By virtue of its convergence, atom economy, and bond-forming efficiency, the methodology documented herein exemplifies the reconciliation of structural complexity and experimental simplicity in the context of medicinal chemistry projects.
Subject(s)
Benzodiazepinones/chemistry , Combinatorial Chemistry Techniques , Molecular Structure , Organic Chemistry Phenomena , StereoisomerismABSTRACT
An expedient and concise Ugi-based approach for the rapid assembly of pyrazin-2(1H)-one-based frameworks has been developed. This convergent approach encompasses skeletal, functional and stereochemical diversity, exhibiting an unusually high bond-forming efficiency as well as high structure and step economies. The method involves the use of readily available commercial reagents and is an example of the reconciliation of structural complexity with operational simplicity in a time- and cost-effective manner.
