title: TAK-063, a PDE10A Inhibitor with Balanced Activation of Direct and Indirect Pathways, Provides Potent Antipsychotic-Like Effects in Multiple Paradigms.
abstract: Phosphodiesterase 10A (PDE10A) inhibitors are expected to be novel drugs for schizophrenia through activation of both direct and indirect pathway medium spiny neurons. However, excess activation of the direct pathway by a dopamine D1 receptor agonist SKF82958 canceled antipsychotic-like effects of a dopamine D2 receptor antagonist haloperidol in methamphetamine (METH)-induced hyperactivity in rats. Thus, balanced activation of these pathways may be critical for PDE10A inhibitors. Current antipsychotics and the novel PDE10A inhibitor TAK-063, but not the selective PDE10A inhibitor MP-10, produced dose-dependent antipsychotic-like effects in METH-induced hyperactivity and prepulse inhibition in rodents. TAK-063 and MP-10 activated the indirect pathway to a similar extent; however, MP-10 caused greater activation of the direct pathway than did TAK-063. Interestingly, the off-rate of TAK-063 from PDE10A in rat brain sections was faster than that of MP-10, and a slower off-rate PDE10A inhibitor with TAK-063-like chemical structure showed an MP-10-like pharmacological profile. In general, faster off-rate enzyme inhibitors are more sensitive than slower off-rate inhibitors to binding inhibition by enzyme substrates. As expected, TAK-063 was more sensitive than MP-10 to binding inhibition by cyclic nucleotides. Moreover, an immunohistochemistry study suggested that cyclic adenosine monophosphate levels in the direct pathway were higher than those in the indirect pathway. These data can explain why TAK-063 showed partial activation of the direct pathway compared with MP-10. The findings presented here suggest that TAK-063's antipsychotic-like efficacy may be attributable to its unique pharmacological properties, resulting in balanced activation of the direct and indirect striatal pathways.
authors: CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors: Kazunori
authors: K
authors: Suzuki
authors: CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors: Akina
authors: A
authors: Harada
authors: CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors: Hirobumi
authors: H
authors: Suzuki
authors: CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.|Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors: Maki
authors: M
authors: Miyamoto
authors: CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors: Haruhide
authors: H
authors: Kimura
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage*; D001921:Brain / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000008:administration & dosage; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006948:Hyperkinesis / Q000139:chemically induced; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage; D008810:Mice, Inbred C57BL; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D065808:Prepulse Inhibition / Q000187:drug effects; D011720:Pyrazoles / Q000008:administration & dosage*; D011724:Pyridazines / Q000008:administration & dosage*; D011804:Quinolines / Q000008:administration & dosage; D017207:Rats, Sprague-Dawley
chemical_list: C000594749:1-(2-fluoro-4-(1H-pyrazol-1-yl)phenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one; C545121:2-((4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy)methyl)quinoline; D014150:Antipsychotic Agents; D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; D011724:Pyridazines; D011804:Quinolines; C000601031:T-773 compound; D008694:Methamphetamine; D016291:Dizocilpine Maleate; D000242:Cyclic AMP; C492284:Pde10a protein, mouse; D010727:Phosphoric Diester Hydrolases; D006152:Cyclic GMP; D004298:Dopamine