Abstract |
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.
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Authors | D W Bonhaus, K K Weinhardt, M Taylor, A DeSouza, P M McNeeley, K Szczepanski, D J Fontana, J Trinh, C L Rocha, M W Dawson, L A Flippin, R M Eglen |
Journal | Neuropharmacology
(Neuropharmacology)
1997 Apr-May
Vol. 36
Issue 4-5
Pg. 621-9
ISSN: 0028-3908 [Print] England |
PMID | 9225287
(Publication Type: Journal Article)
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Chemical References |
- 8-(5-(5-amino-2,4-dimethoxyphenyl)-5-oxopentyl)-1,3,8-triazaspiro(4.5)decane-2,4-dione
- Ligands
- Receptors, Serotonin
- Serotonin Antagonists
- Spiro Compounds
- Sulfonamides
- Hydrogen
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Topics |
- Animals
- CHO Cells
- Cell Membrane
(drug effects, metabolism)
- Cricetinae
- Feeding Behavior
(drug effects)
- Female
- Guinea Pigs
- Humans
- Hydrogen
(metabolism)
- Ligands
- Male
- Motor Activity
(drug effects)
- Radioligand Assay
- Rats
- Rats, Sprague-Dawley
- Receptors, Serotonin
(drug effects, metabolism)
- Serotonin Antagonists
(pharmacology)
- Spiro Compounds
(pharmacology)
- Sulfonamides
(pharmacology)
- Weight Gain
(drug effects)
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