TAK-063, a PDE10A Inhibitor with Balanced Activation of Direct and Indirect Pathways, Provides Potent Antipsychotic-Like Effects in Multiple Paradigms

anon79999497 · February 7, 2016, 5:18pm

ncbi.nlm.nih.gov

TAK-063, a PDE10A Inhibitor with Balanced Activation of Direct and Indirect Pathways, Provides Potent Antipsychotic-Like Effects in Multiple Paradigms.

K Suzuki, A Harada, H Suzuki, M Miyamoto and H Kimura, Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2016 08

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.

BlueFlame · February 7, 2016, 6:24pm

Yes finally I’ve been waiting for a PDE10A Inhibitor. Hope it can make me smarter!

cactustomato · February 7, 2016, 6:39pm

I really hope these end up working because it might be the only medication that doesn’t cause brain damage.

far_cry0 · February 8, 2016, 7:11am

will it help in negative symptoms of sz…

Andrey · February 8, 2016, 7:03pm

It remains to be seen if it alters the negative symptom course. But treating cognitive issues will definitely help many people.

DelusionalSoldier · November 8, 2016, 11:21pm

Another PDE10 Inhibitor that is being investigated is OMS-824. I hope these PDE10 Inhibitors work great :D.

anon11056724 · November 8, 2016, 11:42pm

How long until one of these baby’s comes out?

Anon10 · November 8, 2016, 11:44pm

From what I’ve read they suspended phase 2 trials for this one. Does that mean they are planning to test it further in the future? Maybe if it makes it in Huntingtons the doctors can prescribe it off label.

DelusionalSoldier · November 8, 2016, 11:51pm

Here is the why:

Omeros Corporation has suspended its trial of OMS824, a phosphodiesterase 10 (PDE10) inhibitor being evaluated for treatment of Huntington’s disease. Omeros provided the update in a press release, stating that a nonclinical study in rats showed high free-plasma concentrations — higher than those observed in non-human primates or humans. The company suspended the human clinical trial after submitting the results from the rat study to the Food and Drug Administration (FDA), which requested that Omeros evaluate the rat study and nonclinical studies before restarting the clinical trial.

Gregory A. Demopulos, M.D., chairman and CEO of Omeros, said, “Based on currently available data, we do not believe that the observation in the rats is caused by OMS824. We will work with the FDA and look forward to continuing the Phase 2 Huntington’s trial.”

far_cry0 · November 9, 2016, 9:15am

This means It has failed…???