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.
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.
ACADIA Pharmaceuticals Inc., 3911 Sorrento Valley Blvd., San Diego, CA 92121, USA. kvanover@acadia-pharm.com
Kimberly E
KE
Vanover
David M
DM
Weiner
Malath
M
Makhay
Isaac
I
Veinbergs
Luis R
LR
Gardell
Jelveh
J
Lameh
Andria L
AL
Del Tredici
Fabrice
F
Piu
Hans H
HH
Schiffer
Thomas R
TR
Ott
Ethan S
ES
Burstein
Allan K
AK
Uldam
Mikkel B
MB
Thygesen
Nathalie
N
Schlienger
Carl Magnus
CM
Andersson
Thomas Y
TY
Son
Scott C
SC
Harvey
Susan B
SB
Powell
Mark A
MA
Geyer
Bo-Ragner
BR
Tolf
Mark R
MR
Brann
Robert E
RE
Davis
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001682:Biological Availability; D003001:Cloning, Molecular; D006801:Humans; D008297:Male; D051379:Mice; D041681:NIH 3T3 Cells; D010880:Piperidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D014508:Urea / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
D010880:Piperidines; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D014508:Urea; C510793:pimavanserin