Cargando…
Multi-Target Approach for Drug Discovery against Schizophrenia
Polypharmacology is nowadays considered an increasingly crucial aspect in discovering new drugs as a number of original single-target drugs have been performing far behind expectations during the last ten years. In this scenario, multi-target drugs are a promising approach against polygenic diseases...
Autores principales: | , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6213273/ https://www.ncbi.nlm.nih.gov/pubmed/30309037 http://dx.doi.org/10.3390/ijms19103105 |
_version_ | 1783367731295289344 |
---|---|
author | Kondej, Magda Stępnicki, Piotr Kaczor, Agnieszka A. |
author_facet | Kondej, Magda Stępnicki, Piotr Kaczor, Agnieszka A. |
author_sort | Kondej, Magda |
collection | PubMed |
description | Polypharmacology is nowadays considered an increasingly crucial aspect in discovering new drugs as a number of original single-target drugs have been performing far behind expectations during the last ten years. In this scenario, multi-target drugs are a promising approach against polygenic diseases with complex pathomechanisms such as schizophrenia. Indeed, second generation or atypical antipsychotics target a number of aminergic G protein-coupled receptors (GPCRs) simultaneously. Novel strategies in drug design and discovery against schizophrenia focus on targets beyond the dopaminergic hypothesis of the disease and even beyond the monoamine GPCRs. In particular these approaches concern proteins involved in glutamatergic and cholinergic neurotransmission, challenging the concept of antipsychotic activity without dopamine D(2) receptor involvement. Potentially interesting compounds include ligands interacting with glycine modulatory binding pocket on N-methyl-d-aspartate (NMDA) receptors, positive allosteric modulators of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, positive allosteric modulators of metabotropic glutamatergic receptors, agonists and positive allosteric modulators of α7 nicotinic receptors, as well as muscarinic receptor agonists. In this review we discuss classical and novel drug targets for schizophrenia, cover benefits and limitations of current strategies to design multi-target drugs and show examples of multi-target ligands as antipsychotics, including marketed drugs, substances in clinical trials, and other investigational compounds. |
format | Online Article Text |
id | pubmed-6213273 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-62132732018-11-14 Multi-Target Approach for Drug Discovery against Schizophrenia Kondej, Magda Stępnicki, Piotr Kaczor, Agnieszka A. Int J Mol Sci Review Polypharmacology is nowadays considered an increasingly crucial aspect in discovering new drugs as a number of original single-target drugs have been performing far behind expectations during the last ten years. In this scenario, multi-target drugs are a promising approach against polygenic diseases with complex pathomechanisms such as schizophrenia. Indeed, second generation or atypical antipsychotics target a number of aminergic G protein-coupled receptors (GPCRs) simultaneously. Novel strategies in drug design and discovery against schizophrenia focus on targets beyond the dopaminergic hypothesis of the disease and even beyond the monoamine GPCRs. In particular these approaches concern proteins involved in glutamatergic and cholinergic neurotransmission, challenging the concept of antipsychotic activity without dopamine D(2) receptor involvement. Potentially interesting compounds include ligands interacting with glycine modulatory binding pocket on N-methyl-d-aspartate (NMDA) receptors, positive allosteric modulators of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, positive allosteric modulators of metabotropic glutamatergic receptors, agonists and positive allosteric modulators of α7 nicotinic receptors, as well as muscarinic receptor agonists. In this review we discuss classical and novel drug targets for schizophrenia, cover benefits and limitations of current strategies to design multi-target drugs and show examples of multi-target ligands as antipsychotics, including marketed drugs, substances in clinical trials, and other investigational compounds. MDPI 2018-10-10 /pmc/articles/PMC6213273/ /pubmed/30309037 http://dx.doi.org/10.3390/ijms19103105 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Review Kondej, Magda Stępnicki, Piotr Kaczor, Agnieszka A. Multi-Target Approach for Drug Discovery against Schizophrenia |
title | Multi-Target Approach for Drug Discovery against Schizophrenia |
title_full | Multi-Target Approach for Drug Discovery against Schizophrenia |
title_fullStr | Multi-Target Approach for Drug Discovery against Schizophrenia |
title_full_unstemmed | Multi-Target Approach for Drug Discovery against Schizophrenia |
title_short | Multi-Target Approach for Drug Discovery against Schizophrenia |
title_sort | multi-target approach for drug discovery against schizophrenia |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6213273/ https://www.ncbi.nlm.nih.gov/pubmed/30309037 http://dx.doi.org/10.3390/ijms19103105 |
work_keys_str_mv | AT kondejmagda multitargetapproachfordrugdiscoveryagainstschizophrenia AT stepnickipiotr multitargetapproachfordrugdiscoveryagainstschizophrenia AT kaczoragnieszkaa multitargetapproachfordrugdiscoveryagainstschizophrenia |