Abstract
The new phosphodiesterase 10A inhibitor (PDE10AI) JNJ-42314415 [3-[6-(2-methoxyethyl)pyridin-3-yl]-2-methyl-8-morpholin-4-ylimidazo[1,2-a]pyrazine] was compared with three reference PDE10AIs and eight dopamine 2 (D2) receptor blockers. Despite displaying relatively low PDE10A activity in vitro, JNJ-42314415 was found to be a relatively potent and specific PDE10AI in vivo. The compound was devoid of effects on prolactin release and of receptor interactions associated with other commonly observed adverse effects of available antipsychotics. Similar to D2 receptor blockers, the tested PDE10AIs antagonized stimulant-induced behavior and inhibited conditioned avoidance behavior; these effects were observed at doses close to the ED50 for striatal PDE10A occupancy. Relative to the ED50 for inhibition of apomorphine-induced stereotypy, PDE10AIs blocked conditioned avoidance behavior and behaviors induced by nondopaminergic stimulants (phencyclidine, scopolamine) more efficiently than did D2 receptor blockers; however, they blocked behaviors induced by dopaminergic stimulants (apomorphine, d-amphetamine) less efficiently. PDE10AIs also induced less pronounced catalepsy than D2 receptor blockers. The effects of PDE10A inhibition against dopaminergic stimulants and on catalepsy were potentiated by the D1 antagonist SCH-23390 (8-chloro-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol), suggesting that enhancement of D1 receptor-mediated neurotransmission contributes to the behavioral profile of PDE10AIs. By reducing dopamine D2 and concomitantly potentiating dopamine D1 receptor-mediated neurotransmission, PDE10AIs may show antipsychotic activity with an improved side-effect profile relative to D2 receptor blockers. However, the clinical implications of this dual mechanism must be further explored.
Footnotes
- Received December 2, 2013.
- Accepted January 9, 2014.
This work was supported by Janssen Research and Development, LLC. Most of the data on the D2 receptor blockers were published previously and are included only for comparison and characterization: Langlois X, Megens A, Lavreysen H, Atack J, Cik M, te Riele P, Peeters L, Wouters R, Vermeire J, Hendrickx H, et al. (2012) Pharmacology of JNJ-37822681, a specific and fast-dissociating D2 antagonist for the treatment of schizophrenia. J Pharmacol Exp Ther 342:91–105.
↵This article has supplemental material available at jpet.aspetjournals.org.
- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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