Pharmacological and Behavioral Profile of N-(4-Fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl) Carbamide (2R,3R)-Dihydroxybutanedioate (2:1) (ACP-103), a Novel 5-Hydroxytryptamine2A Receptor Inverse Agonist
| العنوان: | Pharmacological and Behavioral Profile of N-(4-Fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl) Carbamide (2R,3R)-Dihydroxybutanedioate (2:1) (ACP-103), a Novel 5-Hydroxytryptamine2A Receptor Inverse Agonist |
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| المؤلفون: | Scott C. Harvey, Isaac Veinbergs, Kimberly E. Vanover, Carl-Magnus A. Andersson, Allan K. Uldam, David M. Weiner, Fabrice Piu, Bo-Ragner Tolf, Andria L. Del Tredici, Mark A. Geyer, Thomas Son, Robert E. Davis, Malath Makhay, Thomas R. Ott, Mark R. Brann, Jelveh Lameh, Ethan S. Burstein, Nathalie Schlienger, Hans H. Schiffer, Susan B. Powell, Luis R. Gardell, Mikkel B. Thygesen |
| المصدر: | Journal of Pharmacology and Experimental Therapeutics. 317:910-918 |
| بيانات النشر: | American Society for Pharmacology & Experimental Therapeutics (ASPET), 2006. |
| سنة النشر: | 2006 |
| مصطلحات موضوعية: | Pharmacology, Agonist, Ketanserin, Chemistry, medicine.drug_class, Pimavanserin, Radioligand Assay, chemistry.chemical_compound, Mechanism of action, Dopamine receptor D2, medicine, Molecular Medicine, Inverse agonist, medicine.symptom, Receptor, medicine.drug |
| الوصف: | The in vitro and in vivo pharmacological properties of N -(4-fluorophenylmethyl)- N -(1-methylpiperidin-4-yl)- N ′-(4-(2-methylpropyloxy)phenylmethyl)carbamide (2 R ,3 R )-dihydroxybutanedioate (2:1) (ACP-103) are presented. A potent 5-hydroxytryptamine (5-HT)2A receptor inverse agonist ACP-103 competitively antagonized the binding of [3H]ketanserin to heterologously expressed human 5-HT2A receptors with a mean p K i of 9.3 in membranes and 9.70 in whole cells. ACP-103 displayed potent inverse agonist activity in the cell-based functional assay receptor selection and amplification technology (R-SAT), with a mean pIC50 of 8.7. ACP-103 demonstrated lesser affinity (mean p K i of 8.80 in membranes and 8.00 in whole cells, as determined by radioligand binding) and potency as an inverse agonist (mean pIC50 7.1 in R-SAT) at human 5-HT2C receptors, and lacked affinity and functional activity at 5-HT2B receptors, dopamine D2 receptors, and other human monoaminergic receptors. Behaviorally, ACP-103 attenuated head-twitch behavior (3 mg/kg p.o.), and prepulse inhibition deficits (1-10 mg/kg s.c.) induced by the 5-HT2A receptor agonist (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride in rats and reduced the hyperactivity induced in mice by the N -methyl-d-aspartate receptor noncompetitive antagonist 5 H -dibenzo[ a , d ]cyclohepten-5,10-imine (dizocilpine maleate; MK-801) (0.1 and 0.3 mg/kg s.c.; 3 mg/kg p.o.), consistent with a 5-HT2A receptor mechanism of action in vivo and antipsychotic-like efficacy. ACP-103 demonstrated >42.6% oral bioavailability in rats. Thus, ACP-103 is a potent, efficacious, orally active 5-HT2A receptor inverse agonist with a behavioral pharmacological profile consistent with utility as an antipsychotic agent. |
| تدمد: | 1521-0103 0022-3565 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_________::7e7de0fc0198101248cda15fb4bff3ccTest https://doi.org/10.1124/jpet.105.097006Test |
| رقم الانضمام: | edsair.doi...........7e7de0fc0198101248cda15fb4bff3cc |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15210103 00223565 |
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