title: The novel phosphodiesterase 10A inhibitor THPP-1 has antipsychotic-like effects in rat and improves cognition in rat and rhesus monkey.
abstract: Phosphodiesterase 10A (PDE10A) is a novel target for the treatment of schizophrenia that may address multiple symptomatic domains associated with this disorder. PDE10A is highly expressed in the brain and functions to metabolically inactivate the important second messengers cAMP and cGMP. Here we describe effects of a potent and orally bioavailable PDE10A inhibitor [2-(6-chloropyridin-3-yl)-4-(2-methoxyethoxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl](imidazo[1,5-a]pyridin-1-yl)methanone] (THPP-1) on striatal signaling pathways, in behavioral tests that predict antipsychotic potential, and assays that measure episodic-like memory in rat and executive function in rhesus monkey. THPP-1 exhibits nanomolar potency on the PDE10A enzyme, demonstrates excellent pharmacokinetic properties in multiple preclinical animal species, and is selective for PDE10A over other PDE families of enzymes. THPP-1 significantly increased phosphorylation of proteins in the striatum involved in synaptic plasticity, including the a-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor (AMPA) GluR1 subunit, extracellular receptor kinase (ERK), and cAMP-response element binding protein (CREB). THPP-1 produced dose-dependent effects in preclinical assays predictive of antipsychotic activity including attenuation of MK-801-induced psychomotor activation and condition avoidance responding in rats. At similar plasma exposures, THPP-1 significantly increased object recognition memory in rat and attenuated a ketamine-induced deficit in the object retrieval detour task in rhesus monkey. These findings suggest that PDE10A inhibitors have the potential to impact multiple symptomatic domains of schizophrenia including positive symptoms and cognitive impairment. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
authors: Neuroscience, Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486, USA. sean_smith2@merck.com
authors: Sean M
authors: SM
authors: Smith
authors: Jason M
authors: JM
authors: Uslaner
authors: Christopher D
authors: CD
authors: Cox
authors: Sarah L
authors: SL
authors: Huszar
authors: Christopher E
authors: CE
authors: Cannon
authors: Joshua D
authors: JD
authors: Vardigan
authors: Donnie
authors: D
authors: Eddins
authors: Dawn M
authors: DM
authors: Toolan
authors: Monika
authors: M
authors: Kandebo
authors: Lihang
authors: L
authors: Yao
authors: Izzat T
authors: IT
authors: Raheem
authors: John D
authors: JD
authors: Schreier
authors: Michael J
authors: MJ
authors: Breslin
authors: Paul J
authors: PJ
authors: Coleman
authors: John J
authors: JJ
authors: Renger
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D003072:Cognition Disorders / Q000209:etiology / Q000517:prevention & control*; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D056344:Executive Function / Q000187:drug effects; D008253:Macaca mulatta; D008297:Male; D061212:Memory, Episodic; D058990:Molecular Targeted Therapy; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D018697:Nootropic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012559:Schizophrenia / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology
chemical_list: C578113:2-(6-chloropyridin-3-yl)-4-(2-methoxyethoxy)-7,8-dihydropyrido(4,3-d)pyrimidin-6(5H)-yl (imidazo(1,5-a)pyridin-1-yl)methanone; D014150:Antipsychotic Agents; D009419:Nerve Tissue Proteins; D018697:Nootropic Agents; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; C512064:PDE10A protein, rat; D010727:Phosphoric Diester Hydrolases