Abstract
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.
Highlights
Schizophrenia is a severe mental illness, affecting up to 1% of the population, with major public health implications
In this review we present classical and novel drug targets for the treatment of schizophrenia, discuss benefits and limitations of multi-target drugs (MTDs) and their design, as well as present multi-target antipsychotics including marketed compounds, compounds in clinical studies, and other investigational compounds
Amperozide and other antagonists of the serotonin 5-HT2A receptor do not reduce repetitive behaviors induced by apomorphine or high doses of amphetamine. These findings suggest that antipsychotic drugs which are antagonists to 5-HT2A receptor do not cause extrapyramidal side effects, in contrast to first generation drugs, which are devoid of activity to serotonin receptors
Summary
Schizophrenia is a severe mental illness, affecting up to 1% of the population, with major public health implications. It is generally agreed that the symptoms of schizophrenia result from disturbances in neurotransmission involving a significant number of receptors and enzymes, mainly within the dopaminergic, glutamatergic, serotoninergic, and adrenergic systems. In this regard, the dopaminergic hypothesis is still the main concept of the disease and all marketed antipsychotics target dopamine D2 receptor. In order to treat efficiently complex neuropsychiatric diseases such as schizophrenia it is necessary to go beyond the “magic bullet” concept This approach in drug discovery was based on the assumption that single-target drugs are safer as they have fewer side effects due to their selectivity. The literature search for this review was mainly based on searching PubMed database with the search terms: schizophrenia, schizophrenia drug targets, antipsychotics, multi-target antipsychotics, multi-target ligands, multi-target drugs with the focus on the references from the last five years, in particular regarding novel investigational compounds
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