SB 242084, a selective and brain penetrant 5-HT2C receptor antagonist
| Autor: | Martyn D. Wood, Neil Upton, A.M. Brown, Derek N. Middlemiss, Thomas P. Blackburn, K.Y. Avenell, F. Bright, Ian Thomson Forbes, Guy A. Kennett, Brenda K. Trail, T. Stean, Riley Gj, V. Holland, Steven Mark Bromidge |
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| Rok vydání: | 1997 |
| Předmět: |
Male
medicine.medical_specialty Indoles medicine.drug_class Aminopyridines Pharmacology Anxiety Motor Activity Phosphatidylinositols Piperazines Conflict Psychological Rats Sprague-Dawley Cellular and Molecular Neuroscience chemistry.chemical_compound Internal medicine medicine Tumor Cells Cultured Animals Humans Social Behavior 5-HT receptor Electroshock SB-206553 5-HT2 receptor Antagonist Brain Feeding Behavior Receptor antagonist Rats Serotonin Receptor Agonists 5-HT2C receptor Endocrinology chemistry Receptors Serotonin 5-HT2C receptor agonist Serotonin Antagonists SB-242084 |
| Zdroj: | Neuropharmacology. 36(4-5) |
| ISSN: | 0028-3908 |
| Popis: | SB 242084 has a high affinity (pKi 9.0) for the cloned human 5-HT2C receptor and 100- and 158-fold selectivity over the closely related cloned human 5-HT2B and 5-HT2A subtypes respectively. SB 242084 had over 100-fold selectivity over a range of other 5-HT, dopamine and adrenergic receptors. In studies of 5-HT-stimulated phosphatidylinositol hydrolysis using SH-SY5Y cells stably expressing the cloned human 5-HT2C receptor, SB 242084 acted as an antagonist with a pKb of 9.3, which closely resembled its corresponding receptor binding affinity. SB 242084 potently inhibited m-chlorophenylpiperazine (mCPP, 7 mgkg i.p. 20 min pre-test)-induced hypolocomotion in rats, a model of in vivo central 5-HT2C receptor function, with an ID50 of 0.11 mg/kg i.p., and 2.0 mg/kg p.o. SB 242084 (0.1-1 mg/kg i.p.) exhibited an anxiolytic-like profile in the rat social interaction test, increasing time spent in social interaction, but having no effect on locomotion. SB 242084 (0.1-1 mg/kg i.p.) also markedly increased punished responding in a rat Geller-Seifter conflict test of anxiety, but had no consistent effect on unpunished responding. A large acute dose of SB 242084 (30 mg/kg p.o.) had no effect on seizure susceptibility in the rat maximal electroshock seizure threshold test. Also, while SB 242084 (2 and 6 mg/kg p.o. 1 hr pre-test) antagonized the hypophagic response to mCPP, neither acute nor subchronic administration of the drug, for 5 days at 2 or 6 mg/kg p.o. twice daily, affected food intake or weight gain. The results suggest that SB 242084 is the first reported selective potent and brain penetrant 5-HT2C receptor antagonist and has anxiolytic-like activity, but does not possess either proconvulsant or hyperphagic properties which are characteristic of mutant mice lacking the 5-HT2C receptor. |
| Databáze: | OpenAIRE |
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