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The University of Bradford Institutional Repository Schizophrenia: synthetic strategies and recent advances in drug design Item Type Article Authors Azmanova, Maria; Pitto-Barry, Anaïs; Barry, Nicolas P.E. Citation Azmanova M, Pitto-Barry A and Barry NPE (2018) Schizophrenia: synthetic strategies and recent advances in drug design. MedChemComm. 9(5): 759-782. Rights (c) 2018 Royal Society of Chemistry. Full-text reproduced in accordance with the publisher's self-archiving policy. Download date 25/09/2021 12:50:48 Link to Item http://hdl.handle.net/10454/15486 The University of Bradford Institutional Repository http://bradscholars.brad.ac.uk This work is made available online in accordance with publisher policies. Please refer to the repository record for this item and our Policy Document available from the repository home page for further information. To see the final version of this work please visit the publisher’s website. Access to the published online version may require a subscription. Link to publisher version: https://doi.org/10.1039/C7MD00448F Citation: Azmanova M, Pitto-Barry A and Barry NPE (2018) Schizophrenia: synthetic strategies and recent advances in drug design. MedChemComm. 9(5): 759-782. Copyright statement: © 2018 Royal Society of Chemistry. Full-text reproduced in accordance with the publisher's self-archiving policy. Schizophrenia: Synthetic strategies and recent advances in drug design Maria Azmanova, Anaïs Pitto-Barry*, and Nicolas P. E. Barry* School of Chemistry and Biosciences, University of Bradford, Bradford BD7 1DP, United Kingdom. Emails: [email protected]; [email protected] Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X First published on the web Xth XXXXXXXXX 200X DOI: 10.1039/b000000x Abstract Schizophrenia is a complex and unpredictable mental disorder which affects several domains of cognition and behaviour. It is a heterogeneous illness characterised by positive, negative, and cognitive symptoms, often accompanied by signs of depression. In this tutorial review, we discuss recent progress in understanding the target sites and mechanisms of action of second-generation antipsychotic drugs. Progress in identifying and defining target sites has been accelerated recently by advances in neuroscience, and newly developed agents that regulate signalling by the main excitatory neurotransmitters in the brain are surveyed. Examples of novel molecules for the treatment of schizophrenia in preclinical and clinical development and their industrial sponsors are highlighted. 1 Introduction Schizophrenia is one of the most mysterious disorders in psychiatry owing to its complex nature and unpredictable course. The very start of the disorder goes back to the early brain development stage and is known to result from genetic and environmental risk factors. The anatomical changes seen in the brains of patients diagnosed with schizophrenia include differences in volume and alterations of various regions of the brain such as the global, cortical, subcortical regions, white and grey matter. Its complex pathology includes abnormalities in the dopaminergic, serotonergic, glutamatergic and GABAergic (related to the function of γ-aminobutyric acid (GABA) neurotransmitter) systems. Such an heterogeneous (symptoms, course, response to treatment and outcome greatly vary with patients1;2) and complex mental disorder is challenging to cure, but recent progress in genomics, epidemiology and neuroscience2 have opened up new avenues for the design of suitable medications for the minimisation of schizophrenia effects and symptoms. A significant number of clinical trials now involve novel molecules for the treatment of schizophrenia. Some of the current (February 2018) clinical trials are listed in Table 1. Table 1. Some examples of industries/sponsors with molecules in development or clinical trials or approved for clinical use. In many cases more details can be found on the Clinical Trials website: http://www.clinicaltrials.gov/ Industry/ Type of Drug drug/mechanism Targeted outcome Stage Sponsor of action To reduce symptoms of Eli Lilly Dopamine schizophrenia, to treat acute (Generic since Olanzapine Approved antagonist exacerbations, and to treat 2011) early-onset schizophrenia Dopamine To reduce the overall Generic Risperidone Approved antagonist symptoms of schizophrenia 9- Dopamine Janssen hydroxyrisperid antagonist and To treat schizoaffective Approved Pharmaceutica. one Serotonin 2A disorder (Paliperidone) antagonist Otsuka Aripiprazole Partial dopamine To treat acute exacerbations Approved 2 agonist of schizophrenia and for maintenance treatment (relapse prevention) Selective inverse ACADIA Pimavanserin agonist of the To treat positive and Pharmaceuticals Phase III (Nuplazid) serotonin 2A negative symptoms Inc. receptor To provide patients with Mu opioid receptor the strong efficacy of Samidorphan antagonist and olanzapine and a Alkermes, Inc. and olanzapine Phase III Dopamine differentiated safety profile (ALKS 3831) antagonist with favourable weight and metabolic properties Dopamine 2 Sumitomo receptor Dainippon Blonanserin To treat positive and antagonists; Phase III Pharma Co., (DSP-5423P) negative symptoms Serotonin 2A Ltd. receptor antagonists Beth Israel GABA reuptake To correct the brain deficits Deaconess Tiagabine Phase III inhibitor associated with the disease Medical Center To improve attention and 3-[2,4 other neuropsychological VA Office of dimethoxybenzy Orally administered dysfunctions in Research and lidene] nicotinic Phase II schizophrenia, leading to Development anabaseine cholinergic agonist improved psychosocial (DMXB-A) outcome To treat negative symptoms Indiana Selective estrogen and cognitive impairment University and LY500307 receptor beta Phase II associated with Eli Lilly agonist schizophrenia Serotonin 1A To treat the positive and Sunovion receptor agonist; negative symptoms of Pharmaceuticals SEP-363856 Trace amine- schizophrenia, as well as Phase II Inc. associated receptor hallucinations and 1 agonist delusions To increase the L-Carnosine (β- Advanced glycation performance of patients Avraham alanyl-L- end-products with schizophrenia on Phase II Reichenberg histidine) production inhibitor memory and learning training tasks Merck Sharp & MK-8189 Undisclosed To treat acute episode Phase II Dohme Corp. Massachusetts Sodium Release of nitric To treat positive and General Phase II nitroprusside oxide negative symptoms Hospital China Medical D-amino acid NMDA-enhancing To treat treatment-resistant Phase II 3 University oxidase inhibitor agent Schizophrenia Hospital (DAAOI-2) Central Institute Cannabinoid of Mental For maintenance treatment Cannabidiol receptors 1 and 2 Phase II Health, of schizophrenia inverse agonist Mannheim To treat cognitive Astellas Pharma ASP4345 Undisclosed impairment associated with Phase I Inc. schizophrenia Otsuka Pharmaceutical Dopamine 2 partial To treat positive and Development & Brexpiprazole Phase I agonist negative symptoms Commercializati on, Inc. Autifony Selective modulator To treat positive, negative Therapeutics AUT00206 Kv3 potassium and cognitive symptoms of Phase 1 Limited channels schizophrenia Chimeric Adjunct to antipsychotic Brian Miller Siltuximab monoclonal Phase 1 medications antibody Memantine (3,5- University of To improve cognitive dimethyl-1- NMDA receptor California, San impairment and symptoms Phase I adamantanamin antagonists Diego in schizophrenic patients e) NCT0211 L- Treatment of Schizophrenia 8610 University of Dopamine 1, 2, 3 tetrahydropalma with anti-inflammatory and Maryland receptors antagonist In tine antiprotozoal activity developm ent Levetiracetam NCT0264 University of (LEV: (S)-α- Anticonvulsant and To reduce hippocampal 7437 In Colorado, ethyl-2-oxo- antiepileptic drug activity in schizophrenia developm Denver pyrrolidine ent acetamide) The development of antipsychotics started in the 1950s with the approval of chlorpromazine and other ‘typical’ antipsychotics (such as haloperidol). Such a discovery allowed for the first time the de-institutionalisation of patients suffering from psychosis. A second generation of antipsychotics (also named as “atypical”), such as clozapine, became available in the late 1980s. The large number of clinical trials currently recruiting and the continuing quest for finding drugs with novel mechanisms of action arise from the fact that both typical and 4 atypical antipsychotics, although having demonstrated some efficacy, do not treat all symptoms of the disease. Furthermore, the treatment of schizophrenia with antipsychotics is impaired by a number of side effects, such as motor side-effects, weight gain, and sedation. The treatment of the symptoms of schizophrenia is therefore of the utmost complexity, and is a task that can only be undertaken via interdisciplinary collaborations and concerted research efforts between chemists, biologists, and clinicians. In this tutorial review, we provide a brief overview of schizophrenia for non-specialist researchers that have interest in anti-schizophrenia chemical drug design or in the biological evaluation of such drug candidates. In order to introduce some emerging approaches for the treatment of schizophrenia, we survey the synthesis, mode of action, effectiveness and limitations of some of the most clinically used typical and atypical antipsychotics, and we highlight some of the current interests in antipsychotic design. We attempt to focus especially on their interactions with target sites, including glutamatergic signalling and inhibition of key transporters.
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