Document Detail

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-hydroxytryptamine(2A) receptor inverse agonist.
MedLine Citation:
PMID:  16469866     Owner:  NLM     Status:  MEDLINE    
The in vitro and in vivo pharmacological properties of N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103) are presented. A potent 5-hydroxytryptamine (5-HT)(2A) receptor inverse agonist ACP-103 competitively antagonized the binding of [(3)H]ketanserin to heterologously expressed human 5-HT(2A) receptors with a mean pK(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 pIC(50) of 8.7. ACP-103 demonstrated lesser affinity (mean pK(i) of 8.80 in membranes and 8.00 in whole cells, as determined by radioligand binding) and potency as an inverse agonist (mean pIC(50) 7.1 in R-SAT) at human 5-HT(2C) receptors, and lacked affinity and functional activity at 5-HT(2B) receptors, dopamine D(2) 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-HT(2A) 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 5H-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-HT(2A) 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-HT(2A) receptor inverse agonist with a behavioral pharmacological profile consistent with utility as an antipsychotic agent.
Kimberly E Vanover; David M Weiner; Malath Makhay; Isaac Veinbergs; Luis R Gardell; Jelveh Lameh; Andria L Del Tredici; Fabrice Piu; Hans H Schiffer; Thomas R Ott; Ethan S Burstein; Allan K Uldam; Mikkel B Thygesen; Nathalie Schlienger; Carl Magnus Andersson; Thomas Y Son; Scott C Harvey; Susan B Powell; Mark A Geyer; Bo-Ragner Tolf; Mark R Brann; Robert E Davis
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Publication Detail:
Type:  Journal Article     Date:  2006-02-09
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  317     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2006 May 
Date Detail:
Created Date:  2006-04-18     Completed Date:  2006-06-09     Revised Date:  2013-06-04    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  910-8     Citation Subset:  IM    
ACADIA Pharmaceuticals Inc., 3911 Sorrento Valley Blvd., San Diego, CA 92121, USA.
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MeSH Terms
Behavior, Animal / drug effects*
Biological Availability
Cloning, Molecular
NIH 3T3 Cells
Piperidines / pharmacokinetics,  pharmacology*
Radioligand Assay
Rats, Sprague-Dawley
Serotonin 5-HT2 Receptor Antagonists*
Serotonin Antagonists / pharmacokinetics,  pharmacology*
Urea / analogs & derivatives*,  pharmacokinetics,  pharmacology
Reg. No./Substance:
0/Piperidines; 0/Serotonin 5-HT2 Receptor Antagonists; 0/Serotonin Antagonists; 57-13-6/Urea; JZ963P0DIK/Pimavanserin

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