Identification and characterization of pyrrolidine diastereoisomers as potent functional agonists and antagonists of the human melanocortin-4 receptor
| Autor: | Joe A. Tran, Melissa Arellano, Stacy Markison, John Saunders, Ajay Madan, Dragan Marinkovic, Chen Chen, Sam R. J. Hoare, Alan C. Foster, Beth A. Fleck, Jenny Wen, Fabio C. Tucci, Caroline W. Chen, Wanlong Jiang |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Agonist Pyrrolidines medicine.drug_class Stereochemistry Clinical Biochemistry Pharmaceutical Science Carboxamide Biochemistry Eating Structure-Activity Relationship Melanocortin receptor Drug Discovery medicine Animals Humans Receptor Molecular Biology IC50 Dose-Response Relationship Drug Chemistry Organic Chemistry Antagonist Stereoisomerism Amides Rats Melanocortin 4 receptor Kinetics Receptor Melanocortin Type 4 Molecular Medicine Melanocortin |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 18:129-136 |
| ISSN: | 0960-894X |
| Popis: | A series of trans-4-phenylpyrrolidine-3-carboxamides were synthesized and characterized as potent ligands of the human melanocortin-4 receptor. Interestingly, a pair of diastereoisomers 13b displayed potent functional agonist and antagonist activity, respectively. Thus, the 3S,4R-pyrrolidine 13b-1 possessed a Ki of 1.0 nM and an EC50 of 3.8 nM, while its 3R,4S-isomer 13b-2 exhibited a Ki of 4.7 and an IC50 of 64 nM. Both compounds were highly selective over other melanocortin receptor subtypes. The MC4R agonist 13b-1 also demonstrated efficacy in a diet-induced obesity model in rats. |
| Databáze: | OpenAIRE |
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