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The Use of PDE10A and PDE9 Inhibitors for Treating Schizophrenia

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Small Molecule Therapeutics for Schizophrenia

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 13))

Abstract

Schizophrenia (Scz) is a chronic and debilitating neurological disorder that afflicts approximately 1% of the general population with an increased incidence within families. Signs of this disorder typically appear between the ages of 16–30 although rare cases of childhood (<13) onset exist. Diagnosis of scz requires symptoms that persist for a duration of 1 month over a 6-month time period. The broad spectrum of symptoms are typically split into three categories: positive, negative, and cognitive. Implicit within these categories is the difficulty for stand-alone treatment methods, suggesting a combination of pharmacological and psychological treatment strategies is needed to manage this disease. Furthermore, while current pharmaceuticals are moderately effective at managing positive symptoms, the severe side effects lower patient compliance. Additionally, drugs used to treat negative and cognitive symptoms only have modest benefits, at best. Due to these limitations, there is a clear need for novel pharmaceuticals that modulate dysfunctional neurological pathways in scz patients. As such, both academic and pharmaceutical researchers are focused on identifying enzymes that can attenuate neurological signaling in disease-relevant brain regions. Specifically, this chapter will provide an in-depth review of current drug discovery efforts focused on inhibiting phosphodiesterase 10 and 9 (PDE10A, PDE9A, respectively).

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Abbreviations

5′ AMP:

5′ Adenosine monophosphate

5′ GMP:

5′ Guanosine monophosphate

AC:

Adenylate cyclase

AKAP:

A-kinase anchoring protein

ATP:

Adenosine triphosphate

BID:

Bis in die (twice a day)

cAMP:

Cyclic adenosine monophosphate

cGMP:

Cyclic guanosine monophosphate

CNGA2:

Cyclic nucleotide-gated channel alpha 2

CNS:

Central nervous system

CSF:

Cerebral spinal fluid

DG:

2-Deoxy-d-glucose

D1:

Dopamine 1

D2:

Dopamine 2

eNOS:

Endothelial NOS

EPS:

Extrapyramidal side effects

ERK:

Extracellular receptor kinase

FDG-PET:

Fluorodeoxyglucose positron emission tomography

GAF:

cGMP phosphodiesterases Anabaena adenylyl cyclases, and Escherichia coli Fh1A

GC:

Guanylate cyclase

GP:

Globus pallidus

GPCR:

G-protein coupled receptors

h:

Hour

HB:

Hydrogen bond

IP:

Intraperitoneal

KO:

Knock-out

LH:

Lateral habenula

LipE:

Lipophilic binding efficiency

LTP:

Long-term potentiation

mRNA:

Messenger ribonucleic acid

NHP:

Nonhuman primate

nM:

Nanomolar

NMDA:

N-methyl-d-aspartate

nNOS:

Neuronal nitric oxide synthase

NO:

Nitric oxide

NOR:

Novel object recognition

NOS:

Nitric oxide synthase

NR:

Not reported

NT:

Neurotensin

ORD:

Object retrieval detour

PDE:

Phosphodiesterase

PET:

Positron emission tomography

PK:

Pharmacokinetic

PKA:

Protein kinase A

PKG:

Protein kinase G

PO:

Per os

PPI:

Pre-pulse inhibition

QD:

Quaque die (once a day)

SAR:

Structure–activity relationship

scz:

Schizophrenia

sGC:

Soluble guanylate cyclase

SNpr:

Substantia Nigra pars reticulata

THP:

Tetrahydropyran

THPP-1:

Tetrahydropyridopyrimidine

VDW:

Van der Waals

VTA:

Ventral tegmented area

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    Jamison B. Tuttle & Bethany L. Kormos

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    Sylvain Celanire

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    Sonia Poli

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Tuttle, J.B., Kormos, B.L. (2014). The Use of PDE10A and PDE9 Inhibitors for Treating Schizophrenia. In: Celanire, S., Poli, S. (eds) Small Molecule Therapeutics for Schizophrenia. Topics in Medicinal Chemistry, vol 13. Springer, Cham. https://doi.org/10.1007/7355_2014_54

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