Abstract
All marketed antipsychotics act by blocking dopamine D2 receptors. Fast dissociation from D2 receptors may be one of the elements contributing to the lower incidence of extrapyramidal symptoms (EPS) exhibited by newer antipsychotics. Therefore, we screened for specific D2 receptor blockers with a fast rate of dissociation. Radioligand binding experiments identified N- [1-(3,4-difluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine (JNJ-37822681) as a fast-dissociating D2 ligand. Its D2 receptor specificity was high compared with atypical antipsychotics, with little activity at receptors associated with unwanted effects [α1, α2, H1, muscarinic, and 5-hydroxytryptamine (5-HT) type 2C] and for receptors that may interfere with the effects of D2 antagonism (D1, D3, and 5-HT2A). JNJ-37822681 occupied D2 receptors in rat brain at relatively low doses (ED50 0.39 mg/kg) and was effective in animal models of psychosis (e.g., inhibition of apomorphine-induced stereotypy or d-amphetamine/phencyclidine-induced hyperlocomotion). Prolactin levels increased from an ED50 (0.17 mg/kg, peripheral D2 receptors) close to the ED50 required for apomorphine antagonism (0.19 mg/kg, central D2 receptors), suggesting excellent brain disposition and minimal prolactin release at therapeutic doses. JNJ-37822681 induced catalepsy and inhibited avoidance behavior, but with a specificity margin relative to apomorphine antagonism that was larger than that obtained for haloperidol and similar to that obtained for olanzapine. This larger specificity margin (compared with haloperidol) may reflect lower EPS liability and less behavioral suppression after JNJ-37822681. JNJ-37822681 is a novel, potent, specific, centrally active, fast-dissociating D2 antagonist with optimal brain disposition, and it is the first compound that allows the evaluation of the potential value of fast D2 antagonism for the treatment of schizophrenia and bipolar disorder.
Footnotes
This work was funded by Johnson and Johnson Pharmaceutical Research and Development, L.L.C. (Raritan, NJ).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
ABBREVIATIONS:
- AE
- adverse effect
- CAR
- conditioned avoidance response
- EPS
- extrapyramidal symptoms
- ESC
- escape behavior
- 5-HT
- 5-hydroxytryptamine
- hD2
- human D2
- CHO
- Chinese hamster ovary
- PCP
- phencyclidine
- BSA
- bovine serum albumin
- JNJ-37822681
- N-[1-(3,4-difluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine
- SCH23390
- 7-chloro-3-methyl-1-phenyl-1,2,4,5-tetrahydro-3-benzazepin-8-ol
- R037617
- (5-{[4-(diphenylmethyl)piperazin-1-yl]methyl}-1-methyl-1H-benzimidazol-2-yl)methanol
- R091150
- 4-amino-N-{1-[3-(4-fluorophenoxy)propyl]-4-methylpiperidin-4-yl}-2-methoxybenzamide.
- Received December 20, 2011.
- Accepted April 4, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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