Abstract
Schizophrenia is a debilitating mental illness which involves three groups of symptoms, i.e., positive, negative and cognitive, and has major public health implications. According to various sources, it affects up to 1% of the population. The pathomechanism of schizophrenia is not fully understood and current antipsychotics are characterized by severe limitations. Firstly, these treatments are efficient for about half of patients only. Secondly, they ameliorate mainly positive symptoms (e.g., hallucinations and thought disorders which are the core of the disease) but negative (e.g., flat affect and social withdrawal) and cognitive (e.g., learning and attention disorders) symptoms remain untreated. Thirdly, they involve severe neurological and metabolic side effects and may lead to sexual dysfunction or agranulocytosis (clozapine). It is generally agreed that the interactions of antipsychotics with various neurotransmitter receptors are responsible for their effects to treat schizophrenia symptoms. In particular, several G protein-coupled receptors (GPCRs), mainly dopamine, serotonin and adrenaline receptors, are traditional molecular targets for antipsychotics. Comprehensive research on GPCRs resulted in the exploration of novel important signaling mechanisms of GPCRs which are crucial for drug discovery: intentionally non-selective multi-target compounds, allosteric modulators, functionally selective compounds and receptor oligomerization. In this review, we cover current hypotheses of schizophrenia, involving different neurotransmitter systems, discuss available treatments and present novel concepts in schizophrenia and its treatment, involving mainly novel mechanisms of GPCRs signaling.
Highlights
Schizophrenia is an important health issue, affecting almost 1% of the population, frequently with significant social and economic implications, as patients often suffer from unemployment and are homeless
This revised version of dopaminergic hypothesis of schizophrenia may explain some clinical and pharmacological features of the disease, i.e., why the schizophrenia patients do not develop all symptoms of psychosis at once or why antipsychotics exert their therapeutic effects after weeks [22]
The limitations of current antipsychotics are supplemented by reports about involvement of neurtotransmitter systems other than the dopaminergic system, especially glutamate neurotransmission that contributes to the pathomechanism of schizophrenia
Summary
Schizophrenia is an important health issue, affecting almost 1% of the population, frequently with significant social and economic implications, as patients often suffer from unemployment and are homeless. Clozapine has a low nanomolar affinity to several aminergic GPCRs which reflexes the complex pathomechanism of the disease Another important breakthrough in the field was discovery that a specific receptor can couple to a few G proteins and can signal independently on G proteins by occurring in an ensemble of conformations which trigger interaction with biased ligands to downstream effectors. Allosteric modulation of GPCRs has lately been a hot topic in GPCR-oriented drug discovery [13,14] as allosteric mode of action brings important advantages over orthosteric drugs: better receptor or even pathway selectivity and fewer side effects and ceiling effect reducing the risk of overdosage [15] This approach has not yet been exploited for antipsychotics, a positive allosteric modulator (PAM) of dopamine D2 receptor, a peptidomimetic PAOPA, was proven efficient in attenuating symptoms of schizophrenia in animal models [16]. We cover current hypotheses of schizophrenia, involving different neurotransmitter systems, discuss available treatments and present novel concepts in schizophrenia and its treatment, involving mainly novel mechanisms of GPCRs signaling
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