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.

Structure-based virtual screening using a D2 receptor homology model was performed to identify dopamine D2 receptor ligands as potential antipsychotics. From screening a library of 6.5 million compounds, 21 were selected and were subjected to experimental validation. From these 21 compounds tested, ten D2 ligands were identified (47.6% success rate, among them D2 receptor antagonists, as expected) that have additional affinity for other receptors tested, in particular 5-HT2A receptors. The affinity (Ki values) of the compounds ranged from 58 nm to about 24 μM. Similarity and fragment analysis indicated a significant degree of structural novelty among the identified compounds. We found one D2 receptor antagonist that did not have a protonatable nitrogen atom, which is a key structural element of the classical D2 pharmacophore model necessary for interaction with the conserved Asp(3.32) residue. This compound exhibited greater than 20-fold binding selectivity for the D2 receptor over the D3 receptor. We provide additional evidence that the amide hydrogen atom of this compound forms a hydrogen bond with Asp(3.32), as determined by tests of its derivatives that cannot maintain this interaction.

In the present study, identification of chiral 1,3,4-oxadiazol-2-ones as potent and selective FAAH inhibitors has been described. The separated enantiomers showed clear differences in the potency and selectivity toward both FAAH and MAGL. Additionally, the importance of the chirality on the inhibitory activity and selectivity was proven by the simplification approach by removing a methyl group at the 3-position of the 1,3,4-oxadiazol-2-one ring. The most potent compound of the series, the S-enantiomer of 3-(1-(4-isobutylphenyl)ethyl)-5-methoxy-1,3,4-oxadiazol-2(3H)-one (JZP-327A, 51), inhibited human recombinant FAAH (hrFAAH) in the low nanomolar range (IC50 = 11 nM), whereas its corresponding R-enantiomer 52 showed only moderate inhibition toward hrFAAH (IC50 = 0.24 μM). In contrast to hrFAAH, R-enantiomer 52 was more potent in inhibiting the activity of hrMAGL compared to S-enantiomer 51 (IC50 = 4.0 μM and 16% inhibition at 10 μM, respectively). The FAAH selectivity of the compound 51 over the supposed main off-targets, MAGL and COX, was found to be >900-fold. In addition, activity-based protein profiling (ABPP) indicated high selectivity over other serine hydrolases. Finally, the selected S-enantiomers 51, 53, and 55 were shown to be tight binding, slowly reversible inhibitors of the hrFAAH.