RS-102221: a novel high affinity and selective, 5-HT2C receptor antagonist
| Autor: | M. Taylor, C. L. Rocha, P. M. McNeeley, Flippin Lee Allen, David J. Fontana, Douglas W. Bonhaus, K. K. Weinhardt, M. W. Dawson, J. Trinh, A. DeSouza, Richard M. Eglen, K. Szczepanski |
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| Rok vydání: | 1997 |
| Předmět: |
Agonist
Male medicine.medical_specialty medicine.drug_class Guinea Pigs RS-102221 CHO Cells Pharmacology Biology Motor Activity Ligands Weight Gain Rats Sprague-Dawley Cellular and Molecular Neuroscience chemistry.chemical_compound Radioligand Assay Internal medicine Cricetinae medicine Enzyme-linked receptor Functional selectivity Animals Humans Selective receptor modulator Spiro Compounds Receptor Sulfonamides Cell Membrane Feeding Behavior Receptor antagonist Rats Endocrinology chemistry Competitive antagonist Receptors Serotonin Female Serotonin Antagonists Hydrogen |
| Zdroj: | Neuropharmacology. 36(4-5) |
| ISSN: | 0028-3908 |
| Popis: | The 5-HT2C receptor is one of three closely related receptor subtypes in the 5-HT2 receptor family. 5-HT2A and 5-HT2B selective antagonists have been described. However, no 5-HT2C selective antagonists have yet been disclosed. As part of an effort to further explore the function of 5-HT2C receptors, we have developed a selective 5-HT2C receptor antagonist, RS-102221 (a benzenesulfonamide of 8-[5-(5-amino-2,4-dimethoxyphenyl) 5-oxopentyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione). This compound exhibited nanomolar affinity for human (pKi = 8.4) and rat (pKi = 8.5) 5-HT2C receptors. The compound also demonstrated nearly 100-fold selectivity for the 5-HT2C receptor as compared to the 5-HT2A and 5-HT2B receptors. RS-102221 acted as an antagonist in a cell-based microphysiometry functional assay (pA2 = 8.1) and had no detectable intrinsic efficacy. Consistent with its action as a 5-HT2C receptor antagonist, daily dosing with RS-102221 (2 mg/kg intraperitoneal) increased food-intake and weight-gain in rats. Surprisingly, RS-102221 failed to reverse the hypolocomotion induced by the 5-HT2 receptor agonist 1-(3-chlorophenyl)piperazine (m-CPP). It is concluded that RS-102221 is the first selective, high affinity 5-HT2C receptor antagonist to be described. |
| Databáze: | OpenAIRE |
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