RESUMO
The third author's name was mistakenly published with an umlaut (Isabelle Köhler). The correct spelling is "Isabelle Kohler".
RESUMO
Despite substantial research carried out over the last decades, it remains difficult to understand the wide range of pharmacological effects of dopaminergic agents. The dopaminergic system is involved in several neurological disorders, such as Parkinson's disease and schizophrenia. This complex system features multiple pathways implicated in emotion and cognition, psychomotor functions and endocrine control through activation of G protein-coupled dopamine receptors. This review focuses on the system-wide effects of dopaminergic agents on the multiple biochemical and endocrine pathways, in particular the biomarkers (i.e., indicators of a pharmacological process) that reflect these effects. Dopaminergic treatments developed over the last decades were found to be associated with numerous biochemical pathways in the brain, including the norepinephrine and the kynurenine pathway. Additionally, they have shown to affect peripheral systems, for example the hypothalamus-pituitary-adrenal (HPA) axis. Dopaminergic agents thus have a complex and broad pharmacological profile, rendering drug development challenging. Considering the complex system-wide pharmacological profile of dopaminergic agents, this review underlines the needs for systems pharmacology studies that include: i) proteomics and metabolomics analysis; ii) longitudinal data evaluation and mathematical modeling; iii) pharmacokinetics-based interpretation of drug effects; iv) simultaneous biomarker evaluation in the brain, the cerebrospinal fluid (CSF) and plasma; and v) specific attention to condition-dependent (e.g., disease) pharmacology. Such approach is considered essential to increase our understanding of central nervous system (CNS) drug effects and substantially improve CNS drug development.
Assuntos
Dopaminérgicos/farmacologia , Desenvolvimento de Medicamentos/métodos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Receptores Dopaminérgicos/metabolismo , Animais , Biomarcadores/análise , Biomarcadores/metabolismo , Modelos Animais de Doenças , Dopaminérgicos/uso terapêutico , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Cinurenina/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , Norepinefrina/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/patologia , Sistema Hipófise-Suprarrenal/metabolismo , Esquizofrenia/tratamento farmacológico , Esquizofrenia/patologia , Transdução de Sinais/efeitos dos fármacosRESUMO
A considerable number of approved drugs show non-equilibrium binding characteristics, emphasizing the potential role of drug residence times for in vivo efficacy. Therefore, a detailed understanding of the kinetics of association and dissociation of a target-ligand complex might provide crucial insight into the molecular mechanism-of-action of a compound. This deeper understanding will help to improve decision making in drug discovery, thus leading to a better selection of interesting compounds to be profiled further. In this review, we highlight the contributions of the Kinetics for Drug Discovery (K4DD) Consortium, which targets major open questions related to binding kinetics in an industry-driven public-private partnership.