ABSTRACT
Phosphodiesterase 10A (PDE10A) is a dual-substrate PDE that hydrolyzes both cAMP and cGMP. PDE10A is selectively expressed in medium spiny neurons in the striatum, suggesting the potential of PDE10A inhibitors in the treatment of schizophrenia. This study presents the pharmacological profile of a novel PDE10A inhibitor, 2-[(E)-2-(7-fluoro-3-methylquinoxalin-2-yl)vinyl]-6-pyrrolidin-1-yl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine hydrochloride (T-251) in rodent models of schizophrenia. T-251 showed a potent inhibitory activity against human PDE10A (IC50â¯=â¯0.050â¯nmol/L) and showed high selectivity over other PDE families which have over 10,000-fold IC50 values. Oral administration of T-251 (0.1-1.0â¯mg/kg) increased cAMP and cGMP in the striatum in a dose-dependent manner. Oral administration of T-251 attenuated MK-801 induced hyperactivity (ED50â¯=â¯0.68â¯mg/kg) and suppressed conditioned avoidance response (ID50â¯=â¯0.87â¯mg/kg) in rats in a dose dependent manner. Furthermore, T-251 significantly attenuated MK-801 induced prepulse inhibition deficits and cognitive deficits in rats. Unlike haloperidol and olanzapine, T-251 (1.0-30â¯mg/kg) did not cause catalepsy in rats. Moreover, T-251 (0.6 and 6.0â¯mg/kg) did not increase plasma levels of prolactin at 1â¯h after administration, whereas haloperidol and olanzapine significantly increased them. The antipsychotic-like effects and cognitive enhancement of T-251 without catalepsy or plasma prolactin elevation observed in rats suggests that T-251 would be a novel antipsychotic with an improved side-effect profile.
Subject(s)
Antipsychotic Agents/pharmacology , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/metabolism , Schizophrenia/drug therapy , Administration, Oral , Animals , Antipsychotic Agents/administration & dosage , Behavior, Animal/drug effects , COS Cells , Catalepsy/chemically induced , Cattle , Chlorocebus aethiops , Corpus Striatum/metabolism , Cyclic AMP/metabolism , Cyclic GMP/metabolism , Disease Models, Animal , Dizocilpine Maleate/pharmacology , Dogs , Humans , Locomotion/drug effects , Male , Mice , Mice, Inbred C57BL , Phosphodiesterase Inhibitors/administration & dosage , Prepulse Inhibition/drug effects , Prolactin/blood , Rats , Rats, Wistar , Snake VenomsABSTRACT
Firefly luciferase and fatty acyl-CoA synthetase are members of the acyl-CoA synthetase super family, which consists of a large N-terminal domain and a small C-terminal domain. Previously we found that firefly luciferase has fatty acyl-CoA synthetic activity, and also identified that the homolog of firefly luciferase in Drosophila melanogaster (CG6178) is a fatty acyl-CoA synthetase and is not a luciferase. In this study, we constructed chimeric proteins by exchanging the domain between Photinus pyralis luciferase (PpLase) and Drosophila CG6178, and determined luminescence and fatty acyl-CoA synthetic activities. A chimeric protein with the N-terminal domain of PpLase and the C-terminal domain of CG6178 (Pp/Dm) had luminescence activity, showing approximately 4% of the activity of wild-type luciferase. The Pp/Dm protein also had fatty acyl-CoA synthetic activity and the substrate specificity was similar to PpLase. In contrast, a chimeric protein with the N-terminal domain of CG6178 and the C-terminal of PpLase (Dm/Pp) had only fatty acyl-CoA synthetase activity, and the substrate specificity was similar to CG6178. These results suggest that the N-terminal domain of firefly luciferase is essential for substrate recognition, and that the C-terminal domain is indispensable but not specialized for the luminescence reaction.
