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      Advances in Discovery of PDE10A Inhibitors for CNS-Related Disorders. Part 1: Overview of the Chemical and Biological Research

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          Abstract

          Phosphodiesterase 10A (PDE10A) is a double substrate enzyme that hydrolyzes second messenger molecules such as cyclic-3’,5’-adenosine monophosphate (cAMP) and cyclic-3’,5’-guanosine monophosphate (cGMP). Through this process, PDE10A controls intracellular signaling pathways in the mammalian brain and peripheral tissues. Pharmacological, biochemical, and anatomical data suggest that disorders in the second messenger system mediated by PDE10A may contribute to impairments in the central nervous system (CNS) function, including cognitive deficits as well as disturbances of behavior, emotion processing, and movement. This review provides a detailed description of PDE10A and the recent advances in the design of selective PDE10A inhibitors. The results of preclinical studies regarding the potential utility of PDE10A inhibitors for the treatment of CNS-related disorders, such as schizophrenia as well as Huntington’s and Parkinson’s diseases are also summarized.

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          Mammalian cyclic nucleotide phosphodiesterases: molecular mechanisms and physiological functions.

          Mitsi A. Blount, Jackie Corbin, Jasmine Francis (2011)
          The superfamily of cyclic nucleotide (cN) phosphodiesterases (PDEs) is comprised of 11 families of enzymes. PDEs break down cAMP and/or cGMP and are major determinants of cellular cN levels and, consequently, the actions of cN-signaling pathways. PDEs exhibit a range of catalytic efficiencies for breakdown of cAMP and/or cGMP and are regulated by myriad processes including phosphorylation, cN binding to allosteric GAF domains, changes in expression levels, interaction with regulatory or anchoring proteins, and reversible translocation among subcellular compartments. Selective PDE inhibitors are currently in clinical use for treatment of erectile dysfunction, pulmonary hypertension, intermittent claudication, and chronic pulmonary obstructive disease; many new inhibitors are being developed for treatment of these and other maladies. Recently reported x-ray crystallographic structures have defined features that provide for specificity for cAMP or cGMP in PDE catalytic sites or their GAF domains, as well as mechanisms involved in catalysis, oligomerization, autoinhibition, and interactions with inhibitors. In addition, major advances have been made in understanding the physiological impact and the biochemical basis for selective localization and/or recruitment of specific PDE isoenzymes to particular subcellular compartments. The many recent advances in understanding PDE structures, functions, and physiological actions are discussed in this review.
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            Overview of PDEs and their regulation.

            Jun Kotera, K Omori (2007)
            Contraction and relaxation of vascular smooth muscle and cardiac myocytes are key physiological events in the cardiovascular system. These events are regulated by second messengers, cAMP and cGMP, in response to extracellular stimulants. The strength of signal transduction is controlled by intracellular cyclic nucleotide concentrations, which are determined by a balance in production and degradation of cAMP and cGMP. Degradation of cyclic nucleotides is catalyzed by 3',5'-cyclic nucleotide phosphodiesterases (PDEs), and therefore regulation of PDEs hydrolytic activity is important for modulation of cellular functions. Mammalian PDEs are composed of 21 genes and are categorized into 11 families based on sequence homology, enzymatic properties, and sensitivity to inhibitors. PDE families contain many splice variants that mostly are unique in tissue-expression patterns, gene regulation, enzymatic regulation by phosphorylation and regulatory proteins, subcellular localization, and interaction with association proteins. Each unique variant is closely related to the regulation of a specific cellular signaling. Thus, multiple PDEs function as a particular modulator of each cardiovascular function and regulate physiological homeostasis.
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              Quantitative comparison of phosphodiesterase mRNA distribution in human brain and peripheral tissues.

              Viktor Lakics, Eric Karran, Frank G Boess (2010)
              Cyclic nucleotide-specific phosphodiesterases (PDEs) play a critical role in signal transduction by regulating the level of adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP) in cells. The gene expression pattern of a PDE provides important information regarding its role in physiological and pathological processes. In this study, we have established the mRNA expression profile all PDE isoenzymes (PDE1A/B/C, 2A, 3A/B, 4A/B/C/D, 5A, 6A/B/C, 7A/B, 8A/B, 9A, 10A, 11A) in a human cDNA collection consisting of 10 brain regions (parietal, frontal, temporal cortex, hippocampus, striatum, thalamus, hypothalamus, substantia nigra, nucleus accumbens, cerebellum), spinal cord, dorsal root ganglia and 12 peripheral tissues (skeletal muscle, heart, thyroid, adrenal gland, pancreas, bladder, kidney, liver, lung, small intestine, spleen, and stomach). Using quantitative real-time polymerase chain reaction and parallel analysis of a carefully selected group of reference genes, we have determined the relative expression of each PDE isoenzyme across the 24 selected tissues, and also compared the expression of selected PDEs to each other within a given tissue type. Several PDEs show strikingly selective expression (e.g. PDE10A and PDE1B mRNA levels in the caudate nucleus are 20-fold higher than in most other tissues; PDE1C and PDE3A are highly expressed in the heart and PDE8B is expressed very strongly in the thyroid gland). This comprehensive approach provides a coherent and quantitative view of the mRNA expression of the PDE gene family and enables an integration of data obtained with other non-quantitative methods. Copyright © 2010. Published by Elsevier Ltd.
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                Author and article information

                Journal
                Title: Current Drug Targets
                Abbreviated Title: CDT
                Publisher: Bentham Science Publishers Ltd.
                ISSN (Print): 13894501
                Publication date Created: November 27 2018
                Publication date (Print): November 27 2018
                Volume: 20
                Issue: 1
                Pages: 122-143
                Affiliations
                [1 ]Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland
                [2 ]Department of Pharmacokinetics and Physical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland
                Article
                DOI: 10.2174/1389450119666180808105056
                PubMed ID: 30091414
                SO-VID: dba32d3a-b16e-478f-b8a7-190eecc6655b
                Copyright © © 2018
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