Partial D2 receptors agonists - pharmacological aspects, metabolism and use in the treatment of schizophrenia-related psychoses

Abstract

The aim of this article is to review selected information on the latest atypical antipsychotic drugs that are characterized by partial agonism of dopamine D2 receptors: brexpiprazole, aripiprazole, cariprazine and lumateperone. The paper discusses the localization and biochemical aspects of D2 receptors. A particularly important site for neuroleptic interactions is the ventral striatopallidal system and the structures comprising the mesocortical pathway, which, among other things, extends to the frontal lobes exhibiting various structural and functional abnormalities in schizophrenia. The symptomatic and syndromic profile of schizophrenia has been described, along with practical guidelines for clinicians. Both archaic psychopathological divisions (e.g., the dichotomy of positive and negative symptoms, primary and secondary symptoms) and contemporary divisions (ICD-11) were taken into account. Brexpiprazole, which is a quinoline derivative, is structurally very similar to aripiprazole. However, it has a slightly different psychopharmacological mechanism centred around lower dopaminergic activity, which translates into a lower risk of developing extrapyramidal symptoms and stronger serotonergic affinity, implying anxiolytic, antidepressant, and procognitive effects. Cariprazine, which is an N-alkylpiperazine, acts as an antagonist for serotonergic receptors and as an agonist for dopaminergic receptors. Studies indicate that, in addition to schizophrenia, it has satisfactory clinical effects in psychotic states in the elderly and agitation of various etiologies. Lumateperone (ITI-007) stands out from the other discussed in this paper drugs due to its modulation of the glutamatergic system. In the case of its mechanism of action, it is also referred to in scientific literature as a dopamine phosphoprotein modulator. Each of the listed here drugs has the potential to reduce positive (delusions, hallucinations) and negative (cognitive impairment, autism, the "ambi" group) symptoms. Their metabolism mainly involves the CYP3A4 and CYP2D6 enzymes. The use of the drugs analyzed in this paper is not limited to schizophrenia-related psychosis. They also achieve significant clinical effects in certain affective disorders (especially those with psychotic states) and neurodevelopmental units. The prospects for further research into new antipsychotic substances were highlighted, which are likely to focus on modulating the activity of the dopaminergic, serotonergic, and glutamatergic systems.