Discovery and Development of Non-Dopaminergic Agents for the Treatment of Schizophrenia: Overview of the Preclinical and Early Clinical Studies.

Abstract:

:Schizophrenia is a chronic psychiatric disorder that affects about 1 in 100 people around the world and results in persistent emotional and cognitive impairments. Untreated schizophrenia leads to deterioration in quality of life and premature death. Although the clinical efficacy of dopamine D2 receptor antagonists against positive symptoms of schizophrenia supports the dopamine hypothesis of the disease, the resistance of negative and cognitive symptoms to these drugs implicates other systems in its pathophysiology. Many studies suggest that abnormalities in glutamate homeostasis may contribute to all three groups of schizophrenia symptoms. Scientific considerations also include disorders of gamma-aminobutyric acid-ergic and serotonergic neurotransmissions as well as the role of the immune system. The purpose of this review is to update the most recent reports on the discovery and development of non-dopaminergic agents that may reduce positive, negative, and cognitive symptoms of schizophrenia, and may be alternative to currently used antipsychotics. This review collects the chemical structures of representative compounds targeting metabotropic glutamate receptor, gamma-aminobutyric acid type A receptor, alpha 7 nicotinic acetylcholine receptor, glycine transporter type 1 and glycogen synthase kinase 3 as well as results of in vitro and in vivo studies indicating their efficacy in schizophrenia. Results of clinical trials assessing the safety and efficacy of the tested compounds have also been presented. Finally, attention has been paid to multifunctional ligands with serotonin receptor affinity or phosphodiesterase inhibitory activity as novel strategies in the search for dedicated medicines for patients with schizophrenia.

journal_name

Curr Med Chem

authors

Jankowska A,Satała G,Partyka A,Wesołowska A,Bojarski AJ,Pawłowski M,Chłoń-Rzepa G

doi

10.2174/0929867326666190710172002

subject

Has Abstract

pub_date

2019-01-01 00:00:00

pages

4885-4913

issue

25

eissn

0929-8673

issn

1875-533X

pii

CMC-EPUB-99546

journal_volume

26

pub_type

杂志文章,评审
  • Ocular Ciliopathies: Genetic and Mechanistic Insights into Developing Therapies.

    abstract::Developing suitable medicines for genetic diseases requires a detailed understanding of not only the pathways that cause the disease, but also the identification of the genetic components involved in disease manifestation. This article focuses on the complexities associated with ocular ciliopathies - a class of debili...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867325666180917102557

    authors: Shivanna M,Anand M,Chakrabarti S,Khanna H

    更新日期:2019-01-01 00:00:00

  • Chemical connexin impairment in the developing gonad associated with offspring infertility.

    abstract::A dramatical decline in human male reproductive function has been reported for the past 20 years. Many recent epidemiological, clinical and experimental findings suggest that the reproductive dysfunction could result from prenatal and neonatal chemical compound exposure. Even if numerous studies argue for a relationsh...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986711797636117

    authors: Gilleron J,Malassiné A,Carette D,Segretain D,Pointis G

    更新日期:2011-01-01 00:00:00

  • Molecular hybridization: a useful tool in the design of new drug prototypes.

    abstract::Molecular hybridization is a new concept in drug design and development based on the combination of pharmacophoric moieties of different bioactive substances to produce a new hybrid compound with improved affinity and efficacy, when compared to the parent drugs. Additionally, this strategy can result in compounds pres...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986707781058805

    authors: Viegas-Junior C,Danuello A,da Silva Bolzani V,Barreiro EJ,Fraga CA

    更新日期:2007-01-01 00:00:00

  • Development and application of Fourier-transform infrared chemical imaging of tumour in human tissue.

    abstract::Fourier-transform infrared (FT-IR) based mapping and imaging is a fast emerging technology which is being increasingly applied to investigate tissues in the high-throughput mode. The high resolution close to the cellular level, the possibility to determine the bio-distribution of molecules of interest (proteins, pepti...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986709787002664

    authors: Petter CH,Heigl N,Rainer M,Bakry R,Pallua J,Bonn GK,Huck CW

    更新日期:2009-01-01 00:00:00

  • Non peptidic alphavbeta3 antagonists: recent developments.

    abstract::The alphavbeta3 receptor, which are members of the group of the cellular adhesion molecules (CAM), are heterodimeric transmembrane glycoprotein receptors involved in processes such as cell-cell and cell-matrix adhesion, cell migration and signaling. Integrin alphavbeta3 receptor is expressed on almost all cells origin...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867053363522

    authors: Cacciari B,Spalluto G

    更新日期:2005-01-01 00:00:00

  • Managing the liabilities arising from structural alerts: a safe philosophy for medicinal chemists.

    abstract::Bioactivation of xenobiotics can, in certain circumstances, result in the formation of reactive electrophilic species. These reactive metabolites may covalently modify proteins and macromolecules and it has been suggested that protein modification is a key initial step in provoking idiosyncratic adverse drug reactions...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986711796391714

    authors: Edwards PJ,Sturino C

    更新日期:2011-01-01 00:00:00

  • Targeting airway inflammation: novel therapies for the treatment of asthma.

    abstract::It is now widely accepted that airway inflammation is the key factor underlying the pathogenesis of asthma. Inhaled corticosteroids remain the most important anti-inflammatory treatment for asthma. However, they are rather non-specific in their actions and their use raises concerns over side effects and compliance iss...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986706778521779

    authors: Walsh GM

    更新日期:2006-01-01 00:00:00

  • Can breast cancer stem cells evade the immune system?

    abstract::The evidence seems to be growing in favor of the stem cell theory of cancer with the emergence of studies demonstrating the parallel mechanisms of self renewing pathways in stem cells and particular subsets of cancer cells. The finding of leukemia stem cells and subsequently breast cancer stem cells (BCSC) further sup...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986712804485863

    authors: Nahas GR,Patel SA,Bliss SA,Rameshwar P

    更新日期:2012-01-01 00:00:00

  • CMT-3, a non-antimicrobial tetracycline (TC), inhibits MT1-MMP activity: relevance to cancer.

    abstract::Tetracyclines (TCs) and their non-antimicrobial analogs (CMTs) have therapeutic potential to inhibit tissue destructive disease processes, such as cancer invasion and metastasis, by inhibiting certain matrix metalloproteinases. Enhanced matrix metalloproteinase-2 (MMP-2; gelatinase A) activity has been correlated to c...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章

    doi:10.2174/0929867013373660

    authors: Lee HM,Golub LM,Cao J,Teronen O,Laitinen M,Salo T,Zucker S,Sorsa T

    更新日期:2001-02-01 00:00:00

  • L-type voltage-dependent calcium channels as therapeutic targets for neurodegenerative diseases.

    abstract::Ca(2+) is a highly versatile intracellular second messenger in the central nervous system, and regulates many complicated cellular processes, including excitation, plasticity and apoptosis. Influx of Ca(2+) from the extracellular fluid is required for sustained elevation of the cytosolic Ca(2+) concentration and full ...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986712803341430

    authors: Yagami T,Kohma H,Yamamoto Y

    更新日期:2012-01-01 00:00:00

  • Plasmid-mediated quinolone resistance in gram-negative bacterial species: an update.

    abstract::Resistance to quinolones and fluoroquinolones has been increasingly reported among human and veterinary isolates during the last three decades related to their wide clinical use. Until recently, the mechanisms of resistance to quinolones in Enterobacteriaceae were believed to be only chromosome-encoded, i.e. related t...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986709787581879

    authors: Cattoir V,Nordmann P

    更新日期:2009-01-01 00:00:00

  • Development of HIV reservoir targeted long acting nanoformulated antiretroviral therapies.

    abstract::Human immunodeficiency virus (HIV) infection commonly results in a myriad of comorbid conditions secondary to immune deficiency. Infection also affects broad organ system function. Although current antiretroviral therapy (ART) reduces disease morbidity and mortality through effective control of peripheral viral load, ...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867321666140826114135

    authors: Edagwa BJ,Zhou T,McMillan JM,Liu XM,Gendelman HE

    更新日期:2014-01-01 00:00:00

  • Biological Roles of the Eclectic Chromogranin-A-derived Peptide Catestatin.

    abstract:BACKGROUND:Research on Chromogranin A (CGA) and its derived fragments convincingly demonstrated the multifunctional activity of the 21 amino acid peptide named Catestatin (CST: human CGA352-372, bovine CGA344-364, rat CGA367-387). This review aims to provide a synopsis of the current information concerning the biologic...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867324666170616104759

    authors: Pasqua T,Angelone T,Spena A,Cerra MC

    更新日期:2017-01-01 00:00:00

  • How is gene transfection able to improve current chemotherapy? The role of combined therapy in cancer treatment.

    abstract::Despite advances in cancer treatment, a large number of patients eventually develop metastatic disease that is generally incurable. Systemic chemotherapy remains the standard treatment for these patients. Several chemotherapeutic combinations have proven effective in the management of cancer. Paradoxically, although t...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986712800099820

    authors: Prados J,Alvarez PJ,Melguizo C,Rodriguez-Serrano F,Carrillo E,Boulaiz H,Vélez C,Marchal JA,Caba O,Ortiz R,Rama A,Aranega A

    更新日期:2012-01-01 00:00:00

  • The Use of Stilbene Scaffold in Medicinal Chemistry and Multi- Target Drug Design.

    abstract::The stilbene scaffold is a basic element for a number of biologically active natural and synthetic compounds, and it is considered as a privileged structure. Stilbenes exemplified by resveratrol, combretastatin A-4 and pterostilbene are of significant interest for drug research and development because of their potenti...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867323666160517121629

    authors: Giacomini E,Rupiani S,Guidotti L,Recanatini M,Roberti M

    更新日期:2016-01-01 00:00:00

  • Brain nitric oxide and its dual role in neurodegeneration/neuroprotection: understanding molecular mechanisms to devise drug approaches.

    abstract::Nitric oxide (NO) has been established as an important messenger molecule in various steps of brain physiology, from development to synaptic plasticity, learning and memory. However, NO has also been viewed as a major agent of neuropathology when, escaping controlled production it may directly or indirectly promote ox...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867033456792

    authors: Contestabile A,Monti B,Contestabile A,Ciani E

    更新日期:2003-10-01 00:00:00

  • Antisense oligonucleotides: the state of the art.

    abstract::The use of antisense oligonucleotides as therapeutic agents has generated considerable enthusiasm in the research and medical community. Antisense oligonucleotides as therapeutic agents were proposed as far back as in the 1970s when the antisense strategy was initially developed. Nonetheless, it has taken almost a qua...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867054864859

    authors: Aboul-Fadl T

    更新日期:2005-01-01 00:00:00

  • Torsadogenic cardiotoxicity of antipsychotic drugs: a structural feature, potentially involved in the interaction with cardiac HERG potassium channels.

    abstract::Many non-cardiovascular drugs of common clinical use cause, as an unwanted accessory property, the prolongation of the cardiac repolarisation process, due to the block of the HERG (Human Ether-a-go-go Related Gene) potassium channel, responsible for the repolarising I(Kr) current. This delayed cardiac repolarisation p...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867043364351

    authors: Testai L,Bianucci AM,Massarelli I,Breschi MC,Martinotti E,Calderone V

    更新日期:2004-10-01 00:00:00

  • Hyaluronidase inhibitors: a biological and therapeutic perspective.

    abstract::The hyaluronidases (HAases) are a group of less extensively studied glycosidases distributed throughout the animal kingdom and are popularly known as 'spreading factors'. In recent years, HAases received much attention due to their ability to abruptly alter the hyaluronic acid (HA) homeostasis. HAases preferentially d...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986709788453078

    authors: Girish KS,Kemparaju K,Nagaraju S,Vishwanath BS

    更新日期:2009-01-01 00:00:00

  • Linear Peptides in Intracellular Applications.

    abstract::To this point, efforts to develop therapeutic peptides for intracellular applications were guided by the perception that unmodified linear peptides are highly unstable and therefore structural modifications are required to reduce proteolytic breakdown. Largely, this concept is a consequence of the fact that most resea...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867324666170508143523

    authors: Zuconelli CR,Brock R,Adjobo-Hermans MJW

    更新日期:2017-01-01 00:00:00

  • IAP Proteins Antagonist: An Introduction and Chemistry of Smac Mimetics under Clinical Development.

    abstract:BACKGROUND:Smac mimetics (also known as IAP antagonist) are a new class of targeted drugs having a goal to suppress the IAPs, reestablishing the apoptotic pathways and inducing cancer cell death. Therefore, development of Smac mimetics was considered an attractive strategy for the development of new anticancer drugs. L...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867325666180313112229

    authors: Ali R,Singh S,Haq W

    更新日期:2018-01-01 00:00:00

  • Highlights in Endocytosis of Nanostructured Systems.

    abstract::The focus of this review is the cellular internalisation mechanism of nanostructured systems (NSs) and their endosomal escape for targeted drug delivery. Endocytosis is a cellular process of internalisation of different molecules and foreign microorganisms. It is currently being studied for drug delivery through nanos...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867324666170214111205

    authors: Voltan AR,Alarcon KM,Fusco-Almeida AM,Soares CP,Mendes-Giannini MJS,Chorilli M

    更新日期:2017-01-01 00:00:00

  • The Role of Universal Stress Proteins in Bacterial Infections.

    abstract::Universal stress proteins are ubiquitously expressed in bacteria, archaea and plants and other eukaryotes. A general property of USPs is their role in adaptation of bacteria to oxidative stress, high temperature, low pH and/or hypoxia. There is increasing evidence that these proteins facilitate the adaption of bacteri...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867324666170124145543

    authors: O'Connor A,McClean S

    更新日期:2017-11-24 00:00:00

  • Flavonoid antioxidants.

    abstract::In order to ascertain the role of dietary flavonoids as antioxidants in vivo it is necessary to understand the chemical nature of the absorbed forms in the circulation in vivo and how the multiplicity of research findings in vitro reflect the bioactivity of flavonoids in vivo. Only when we gain adequate information on...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867013373011

    authors: Rice-Evans C

    更新日期:2001-06-01 00:00:00

  • Bis-quinolinium cyclophanes: highly potent and selective non-peptidic blockers of the apamin-sensitive Ca2+-activated K+ channel.

    abstract::Small conductance Ca(2+)-activated K(+) (SK(Ca)) channels comprise an important subclass of K(+) channels. Selective blockade of SK(Ca) channels may find application in the therapy of myotonic muscular dystrophy, gastrointestinal dysmotilities, memory disorders, narcolepsy, and alcohol abuse. In the cyclophanes descri...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/092986708784534983

    authors: Conejo-García A,Campos JM

    更新日期:2008-01-01 00:00:00

  • Terpenes, Phenylpropanoids, Sulfur and Other Essential Oil Constituents as Inhibitors of Cholinesterases.

    abstract::Essential oils constituents are a diverse family of low molecular weight organic compounds with comprehensive biological activity. According to their chemical structure, these active compounds can be divided into four major groups: terpenes, terpenoids, phenylpropenes, and "others". In addition, they may contain diver...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867325666180330092607

    authors: Burčul F,Blažević I,Radan M,Politeo O

    更新日期:2020-01-01 00:00:00

  • p27(kip1) functional regulation in human cancer: a potential target for therapeutic designs.

    abstract::The mitotic cell cycle is a tightly regulated process that ensures the correct division of one cell into two daughter cells. Progress along the different phases of the cell cycle is positively regulated by the sequential activation of a family of serine-threonine kinases called CDKs (Cyclin Dependent Kinases). Their a...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867054367149

    authors: Belletti B,Nicoloso MS,Schiappacassi M,Chimienti E,Berton S,Lovat F,Colombatti A,Baldassarre G

    更新日期:2005-01-01 00:00:00

  • Neurotrophins' Modulation by Olive Polyphenols.

    abstract:BACKGROUND:Polyphenols are probably the most known and investigated molecules of nutritional interest as micronutrients present in abundance in our diet. Some of the most important food sources of polyphenols in the Mediterranean diet are olives and olive oil. A growing body of evidence from animal models to clinical s...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867323666160627104022

    authors: Carito V,Ceccanti M,Tarani L,Ferraguti G,Chaldakov GN,Fiore M

    更新日期:2016-01-01 00:00:00

  • Visible Blue Light Therapy: Molecular Mechanisms and Therapeutic Opportunities.

    abstract:BACKGROUND:Visible light is absorbed by photoacceptors in pigmented and non-pigmented mammalian cells, activating signaling cascades and downstream mechanisms that lead to the modulation of cellular processes. Most studies have investigated the molecular mechanisms and therapeutic applications of UV and the red to near...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867324666170727112206

    authors: Garza ZCF,Born M,Hilbers PAJ,van Riel NAW,Liebmann J

    更新日期:2018-01-01 00:00:00

  • The seemingly trivial yet challenging synthesis of poly(aminoester) dendrimers.

    abstract::Poly(aminoester) dendrimers are expected to hold great promise as biodegradable nanocarriers for drug delivery due to their advantageous properties allowing their biodegradability, potentially lower toxicity and possibility of diverse chemical conjugations. The synthetic strategies for constructing such dendrimers inc...

    journal_title:Current medicinal chemistry

    pub_type: 杂志文章,评审

    doi:10.2174/0929867311209025011

    authors: Wang Y,Quelever G,Peng L

    更新日期:2012-01-01 00:00:00