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Open AccessReview

Multi-Target Approach for Drug Discovery against Schizophrenia

1
Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodźki St., Lublin PL-20093, Poland
2
School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, P.O. Box 1627, Kuopio FI-70211, Finland
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(10), 3105; https://doi.org/10.3390/ijms19103105
Received: 3 September 2018 / Revised: 4 October 2018 / Accepted: 6 October 2018 / Published: 10 October 2018
(This article belongs to the Special Issue Molecular Psychiatry)
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 D2 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. View Full-Text
Keywords: antipsychotics; drug design; multi-target drugs; polypharmacology; schizophrenia antipsychotics; drug design; multi-target drugs; polypharmacology; schizophrenia
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MDPI and ACS Style

Kondej, M.; Stępnicki, P.; Kaczor, A.A. Multi-Target Approach for Drug Discovery against Schizophrenia. Int. J. Mol. Sci. 2018, 19, 3105.

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