Autoradiographic studies of RP 62203, a potent 5-HT2 receptor antagonist. In vitro and ex vivo selectivity profile.
In this study, quantitative autoradiography was used to determine the selectivity of RP 62203, a novel naphtosultam derivative, for 5-HT2 receptors in vitro and ex vivo, using [125I]7-amino-8-iodo-ketanserin ([125I]AMIK) and [3H]mesulergine as radioligands. The density of [125I]AMIK or [3H]mesulergine binding sites was determined by quantitative image analysis. In in vitro experiments, RP 62203 displaced [125I]AMIK from 5-HT2 receptors with an IC50 of 0.21 nM in rat frontal cortex. Its affinity for 5-HT1C receptors was 100-fold lower (IC50 25 nM versus [3H]mesulergine in rat choroid plexus). RP 62203 showed moderate affinity for alpha 1-adrenoceptors in the rat thalamus (IC50 14 nM) and for histamine H1 receptors in the guinea-pig cerebellum (IC50 13 nM). The tetrabenazine sites were not affected by RP 62203 at a concentration of 30 nM. In ex vivo experiments, RP 62203 was about 4 times more potent than ritanserin in displacing [125I]AMIK from 5-HT2 receptors (ED50 0.58 mg/kg p.o.). A dose of 10 mg/kg of RP 62203 did not displace [3H]mesulergine from 5-HT1C receptors or [125I]AMIK from alpha 1-adrenoceptors and tetrabenazine sites in the rat brain and from histamine H1 receptors in the guinea-pig brain. These results demonstrate that RP 62203 specifically recognizes 5-HT2 receptors in rodent brain.
Rhône-Poulenc Rorer, Centre de Recherche de Vitry-Alfortville, Vitry-sur-Seine, France.
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Malgouris
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Flamand
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Doble
D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D001345:Autoradiography; D002531:Cerebellum / Q000378:metabolism; D002831:Choroid Plexus / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D003499:Cyclic S-Oxides / Q000494:pharmacology*; D004873:Ergolines / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007650:Ketanserin / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013788:Thalamus / Q000378:metabolism
D000978:Antiparkinson Agents; D003499:Cyclic S-Oxides; D004873:Ergolines; D009281:Naphthalenes; D011942:Receptors, Adrenergic, alpha; D012702:Serotonin Antagonists; C050315:7-amino-8-iodoketanserin; C070475:fananserin; D007650:Ketanserin; C031649:mesulergine