title: Deramciclane, a putative anxiolytic drug, is a serotonin 5-HT2C receptor inverse agonist but fails to induce 5-HT2C receptor down-regulation.
abstract: Deramciclane (EGIS-3886) is a novel anxiolytic agent that binds with high affinity to 5-HT2A/2C receptors. The interactions of deramciclane with the serotonin 5-HT2C receptor were characterized further using receptor phosphoinositide hydrolysis assays and receptor autoradiography. Deramciclane antagonized 5-HT2C receptor mediated 5-HT-stimulated phosphoinositide hydrolysis with an IC50 value of 168 nM. Deramciclane also decreased basal phosphoinositide hydrolysis by up to 33% (EC50 = 93 nM) in a physiological system in the choroid plexus, suggesting that deramciclane possesses inverse agonist properties at this receptor. Administration of single doses of 0.5 mg/kg and 10 mg/kg resulted in a maximal 5-HT2C receptor occupancy of up to 45% and 79%, respectively, in the choroid plexus. Chronic (14 days) treatment with 0.5 mg/kg or 10 mg/kg deramciclane did not alter [125I]DOI (agonist) or [3H]mesulergine (antagonist) binding to 5-HT2C receptors in the choroid plexus compared to saline-treated controls, as determined by quantitative receptor autoradiography. In comparison, the effects of deramciclane on 5-HT2A binding characteristics and receptor occupancy were also studied. Deramciclane treatment resulted in 5-HT2A receptor occupancy of up to 78%, but no significant effect of chronic treatment on 5-HT2A receptor agonist binding levels was found. In conclusion, these data indicate that deramciclane is a 5-HT2C receptor inverse agonist and occupies 5-HT2C receptors during treatment, and that chronic treatment with deramciclane does not lead to 5-HT2C receptor down-regulation.
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, University of Turku School of Medicine, Finland. eepee@utu.fi
authors.forename: E P
authors.initials: EP
authors.lastname: Pälvimäki
authors.forename: H
authors.initials: H
authors.lastname: Majasuo
authors.forename: M
authors.initials: M
authors.lastname: Kuoppamäki
authors.forename: P T
authors.initials: PT
authors.lastname: Männistö
authors.forename: E
authors.initials: E
authors.lastname: Syvälahti
authors.forename: J
authors.initials: J
authors.lastname: Hietala
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D001892:Camphanes / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology*
chemical_list: D014151:Anti-Anxiety Agents; D001892:Camphanes; D007295:Inositol Phosphates; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D003024:Clozapine; C060555:deramciclane