title: Pharmacology of JNJ-42314415, a centrally active phosphodiesterase 10A (PDE10A) inhibitor: a comparison of PDE10A inhibitors with D2 receptor blockers as potential antipsychotic drugs.
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 (D(2)) 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 D(2) receptor blockers, the tested PDE10AIs antagonized stimulant-induced behavior and inhibited conditioned avoidance behavior; these effects were observed at doses close to the ED(50) for striatal PDE10A occupancy. Relative to the ED(50) for inhibition of apomorphine-induced stereotypy, PDE10AIs blocked conditioned avoidance behavior and behaviors induced by nondopaminergic stimulants (phencyclidine, scopolamine) more efficiently than did D(2) receptor blockers; however, they blocked behaviors induced by dopaminergic stimulants (apomorphine, d-amphetamine) less efficiently. PDE10AIs also induced less pronounced catalepsy than D(2) receptor blockers. The effects of PDE10A inhibition against dopaminergic stimulants and on catalepsy were potentiated by the D(1) antagonist SCH-23390 (8-chloro-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol), suggesting that enhancement of D(1) receptor-mediated neurotransmission contributes to the behavioral profile of PDE10AIs. By reducing dopamine D(2) and concomitantly potentiating dopamine D(1) receptor-mediated neurotransmission, PDE10AIs may show antipsychotic activity with an improved side-effect profile relative to D(2) receptor blockers. However, the clinical implications of this dual mechanism must be further explored.
authors.affiliation: Janssen Research & Development, a Division of Janssen Pharmaceutica, NV Beerse, Belgium.
authors.forename: Anton A H P
authors.initials: AA
authors.lastname: Megens
authors.forename: Herman M R
authors.initials: HM
authors.lastname: Hendrickx
authors.forename: Koen A
authors.initials: KA
authors.lastname: Hens
authors.forename: Ineke
authors.initials: I
authors.lastname: Fonteyn
authors.forename: Xavier
authors.initials: X
authors.lastname: Langlois
authors.forename: Ilse
authors.initials: I
authors.lastname: Lenaerts
authors.forename: Marijke V F
authors.initials: MV
authors.lastname: Somers
authors.forename: Peter
authors.initials: P
authors.lastname: de Boer
authors.forename: Greet
authors.initials: G
authors.lastname: Vanhoof
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D018492:Dopamine Antagonists / Q000737:chemistry / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism*; D011388:Prolactin / Q000378:metabolism; D011485:Protein Binding; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D061987:Sf9 Cells; D018411:Spodoptera; D013239:Stereotyped Behavior / Q000187:drug effects
chemical_list: C588265:3-(6-(2-methoxyethyl)pyridin-3-yl)-2-methyl-8-morpholin-4-ylimidazo(1,2-a)pyrazine; D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D011719:Pyrazines; D011388:Prolactin; C119843:PDE10A protein, human; C512064:PDE10A protein, rat; D010727:Phosphoric Diester Hydrolases