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Antipsychotic Drugs
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Harleen Kaur, Ramneek Kaur, Varsha Rani, Kanishka Sharma, Pawan Kumar Maurya
The antipsychotic drugs bind mainly to DA, precisely dopamine receptor 2 (D2) as antipsychotic drugs can mediate through the potential site. The dopamine hypothesis is led by the association between neuroleptic drugs and D2, DA receptors for schizophrenia. Therefore, the development of drugs is focused to act at central DA receptors (Maurya et al., 2017). Recently, some atypical antipsychotic drugs, which are prototypic in nature like clozapine, focus on central receptors rather DA receptors. The reason behind the above fact is that as per the data indicated by in vitro binding clozapine was made to compare with most typical antipsychotic drugs and haloperidol and it was found that clozapine has low affinity for D2, DA receptors. Apart from D2 receptors the affinity of the site of action for clozapine also led to modification in DA and dopamine hypothesis for schizophrenia. The chapter focuses on the mechanism of action of various antipsychotic drugs like clozapine, raclopride, remoxipride, etc. Further, the comparison between first-generation antipsychotic and second-generation antipsychotic drugs has been described.
The Nucleus Accumbens Core and Shell: Accumbal Compartments and Their Functional Attributes
Published in Peter W. Kalivas, Charles D. Barnes, Limbic Motor Circuits and Neuropsychiatry, 2019
Ariel Y. Deutch, Andrea J. Bourdelais, Daniel S. Zahm
These pharmacological studies were followed by examination of the effects of typical and atypical APDs on striatal Fos expression.127 Rats were treated with haloperidol or clozapine. In addition, we examined the effects of the new putative atypical agent, remoxipride,132–134 and also studied the effects of metaclopramide, a substituted benzamide that blocks D2 receptors and has severe EPS liability135,136 but has not been demonstrated in controlled studies to be a clinically effective APD.137,138 Haloperidol increased Fos expression soon after injection in the dorsolateral and (to a lesser degree) medial striatum, and it increased the number of Fos-li neurons in the septal pole (cone), shell, and core of the NAS.127,139,140 In contrast, clozapine did not significantly alter Fos expression in the dorsal striatum, and increased the number of Fos-li neurons in the accumbal shell and septal pole, but not the core. The effects of the putative atypical APD remoxipride were very similar to clozapine, leading to increased numbers of Fos-li cells in the shell and septal pole, but not the core, of the NAS; remoxipride also increased Fos expression in the medial periventricular (but not dorsolateral striatum). Finally, metaclopramide increased Fos expression in the dorsal striatum, but within the NAS only increased the number of Fos-li cells in the septal pole, but not in the shell or core. These effects are summarized in Table 2.
Bundling arrows: improving translational CNS drug development by integrated PK/PD-metabolomics
Published in Expert Opinion on Drug Discovery, 2018
W. J. van den Brink, T. Hankemeier, P. H. van der Graaf, E. C. M. de Lange
In addition to longitudinal evaluation of the pharmacometabolomics response, the integration with PK/PD modeling has been shown in a few studies. Clustering of longitudinal transcriptomics data formed the basis for the 6 turnover models in one study. Together, these turnover models formed a complex PK/PD model that described the gene-expression signaling cascade in the rat liver after corticosteroid treatment [84]. In another study, clustering was applied to the PK/PD parameters identified from pharmacometabolomics data in rats after remoxipride treatment [95]. This analysis revealed 6 unique PK/PD relations, 18 potential biomarkers and two perturbed pathways (Figure 3). It has the potential to define a therapeutic window on basis of multiple biomarkers, provides a list of biomarkers to take into account in additional studies, and gives insight into biological effects of remoxipride. The application of such analysis in multiple species will give insights into species differences on the PK/PD parameters that describe the longitudinal pharmacometabolomics response. Depending on the differences in parameters, dosing strategies can be defined following simulation of worst-to-best case scenarios as was performed by Gosset et al. [57] for the effect of a Transient Receptor Potential Melastatin-8 (TRPM8) blocker on a single marker (core body temperature). Eventually, pharmacometabolomics data analysis methods can aid the development of quantitative systems pharmacology (QSP) models which aim to mathematically describe the interactions between multiple elements of the biological system (e.g. biomolecules, cells, tissues) in order to understand the impact of drugs on the system as a whole [91,96,97]. Quantitative metabolic networks can provide a topological basis of QSP models to be integrated with organ-level networks, receptor binding kinetics and PK [91,97]. QSP models are promising for interspecies translation by humanizing the animal-based model parameters [9,98,99].