Phosphodiesterase 10A (PDE10A) is a novel target for the treat
ment of schizophrenia that
may address
multiple sy
mpto
matic do
mains associated with this disorder. PDE10A is highly expressed in the brain and functions to
metabolically inactivate the i
mportant 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]pyri
midin-6(5H)-yl](i
midazo[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
me
mory in rat and executive function in rhesus
monkey. THPP-1 exhibits nano
molar potency on the PDE10A enzy
me, de
monstrates excellent phar
macokinetic properties in
multiple preclinical ani
mal species, and is selective for PDE10A over other PDE fa
milies of enzy
mes. THPP-1 significantly increased phosphorylation of proteins in the striatu
m involved in synaptic plasticity, including the a-a
mino-3-hydroxy-5-
methylisoxazole-4-proprionic acid receptor (AMPA) GluR1 subunit, extracellular receptor kinase (ERK), and cAMP-response ele
ment binding protein (CREB). THPP-1 produced dose-dependent effects in preclinical assays predictive of antipsychotic activity including attenuation of MK-801-induced psycho
motor activation and condition avoidance responding in rats. At si
milar plas
ma exposures, THPP-1 significantly increased object recognition
me
mory in rat and attenuated a keta
mine-induced deficit in the object retrieval detour task in rhesus
monkey. These findings suggest that PDE10A inhibitors have the potential to i
mpact
multiple sy
mpto
matic do
mains of schizophrenia including positive sy
mpto
ms and cognitive i
mpair
ment.
This article is part of a Special Issue entitled ¡®Cognitive Enhancers¡¯.