Allosteric Modulators of G Protein-Coupled Dopamine and Serotonin Receptors: A New Class of Atypical Antipsychotics

Fasciani, Irene; Petragnano, Francesco; Aloisi, Gabriella; Marampon, Francesco; Carli, Marco De; Scarselli, Marco; Maggio, Roberto; Rossi, Mario

doi:10.3390/ph13110388

Cited by 20 publications

(16 citation statements)

References 150 publications

(199 reference statements)

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“…Regarding the mechanism of action, AAPs are weak D 2 receptor blockers and they act beyond D 2 antagonism, involving other receptor targets (e.g., serotonin (5-HT) receptors) [ 13 , 14 , 15 , 16 ]. The ratio of 5-HT 2A /D 2 and 5-HT 2C /D 2 receptor affinity together with a rapid dissociation constant (Koff) from the D 2 receptor are two important factors that distinguish AAPs in terms of efficacy and side effects [ 17 , 18 ].…”

Section: A New Classification For Aaps: the Spectrum Of Atypiamentioning

confidence: 99%

Atypical Antipsychotics and Metabolic Syndrome: From Molecular Mechanisms to Clinical Differences

et al. 2021

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Atypical antipsychotics (AAPs) are commonly prescribed medications to treat schizophrenia, bipolar disorders and other psychotic disorders. However, they might cause metabolic syndrome (MetS) in terms of weight gain, dyslipidemia, type 2 diabetes (T2D), and high blood pressure, which are responsible for reduced life expectancy and poor adherence. Importantly, there is clear evidence that early metabolic disturbances can precede weight gain, even if the latter still remains the hallmark of AAPs use. In fact, AAPs interfere profoundly with glucose and lipid homeostasis acting mostly on hypothalamus, liver, pancreatic β-cells, adipose tissue, and skeletal muscle. Their actions on hypothalamic centers via dopamine, serotonin, acetylcholine, and histamine receptors affect neuropeptides and 5′AMP-activated protein kinase (AMPK) activity, thus producing a supraphysiological sympathetic outflow augmenting levels of glucagon and hepatic glucose production. In addition, altered insulin secretion, dyslipidemia, fat deposition in the liver and adipose tissues, and insulin resistance become aggravating factors for MetS. In clinical practice, among AAPs, olanzapine and clozapine are associated with the highest risk of MetS, whereas quetiapine, risperidone, asenapine and amisulpride cause moderate alterations. The new AAPs such as ziprasidone, lurasidone and the partial agonist aripiprazole seem more tolerable on the metabolic profile. However, these aspects must be considered together with the differences among AAPs in terms of their efficacy, where clozapine still remains the most effective. Intriguingly, there seems to be a correlation between AAP’s higher clinical efficacy and increase risk of metabolic alterations. Finally, a multidisciplinary approach combining psychoeducation and therapeutic drug monitoring (TDM) is proposed as a first-line strategy to avoid the MetS. In addition, pharmacological treatments are discussed as well.

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Section: A New Classification For Aaps: the Spectrum Of Atypiamentioning

confidence: 99%

Atypical Antipsychotics and Metabolic Syndrome: From Molecular Mechanisms to Clinical Differences

et al. 2021

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“…There are also neutral or silent allosteric modulators (SAMs) that bind to the receptor and display no measurable changes in function ( Lindsley et al, 2016 ) but can block the effects of PAMs or NAMS ( Rodriguez et al, 2005 ). There are now many GPCR allosteric modulators that have been developed ( Chen et al, 2008 ; Wold et al, 2019 ; Zhou and Cunningham, 2019 ; Fasciani et al, 2020 ) with several in clinical trials or with FDA approval ( Wold et al, 2019 ). The HIV entry inhibitor maraviroc is the most known clinically used GPCR allosteric modulator against the CCR5 receptor ( Maeda et al, 2012 ).…”

Section: Pharmacological Interventionsmentioning

confidence: 99%

Current Developments on the Role of α1-Adrenergic Receptors in Cognition, Cardioprotection, and Metabolism

Perez

2021

Front. Cell Dev. Biol.

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The α1-adrenergic receptors (ARs) are G-protein coupled receptors that bind the endogenous catecholamines, norepinephrine, and epinephrine. They play a key role in the regulation of the sympathetic nervous system along with β and α2-AR family members. While all of the adrenergic receptors bind with similar affinity to the catecholamines, they can regulate different physiologies and pathophysiologies in the body because they couple to different G-proteins and signal transduction pathways, commonly in opposition to one another. While α1-AR subtypes (α1A, α1B, α1C) have long been known to be primary regulators of vascular smooth muscle contraction, blood pressure, and cardiac hypertrophy, their role in neurotransmission, improving cognition, protecting the heart during ischemia and failure, and regulating whole body and organ metabolism are not well known and are more recent developments. These advancements have been made possible through the development of transgenic and knockout mouse models and more selective ligands to advance their research. Here, we will review the recent literature to provide new insights into these physiological functions and possible use as a therapeutic target.

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“…However, direct early studies with serotonergic agonists and antagonists failed to improve cognitive impairments, most likely due to a lack of subtype specificity [415]. Despite the potential of allosteric serotonergic modulators, so far there is still a relatively limited number of pre-clinical studies examining PAMs and NAMs in the context of cognitive impairments [416].…”

Section: Serotonergic Systemmentioning

confidence: 99%

Recent Developments in Treating Cognitive Impairment Associated with Schizophrenia

Bittner¹,

Barnes-Scheufler²,

Hettwer³

et al. 2021

Preprint

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Pervasive and wide-ranging cognitive deficits are a core feature of schizophrenia and an important determinant of long-term functional outcome. The lack of sufficiently effective treatments for cognitive impairment associated with schizophrenia (CIAS) represents a major unmet need and a central roadblock towards recovery. This is partly due to the current therapeutic focus on clinical symptoms, and the relative neglect of cognitive impairments despite their functionally disabling effects. Furthermore, effective treatment is impeded by our limited knowledge of the complex pathophysiology, which gives rise to perturbed information processing. Here, we review mechanisms and effectiveness of available pharmacological and non-pharmacological treatments for CIAS. Current evidence indicates, that while techniques which broadly enhance neural plasticity show the greatest therapeutic potential, effect sizes are at best moderate. Among other reasons, this is due to a considerable heterogeneity of responses to individual interventions. Furthermore, we discuss how recent conceptual advances in operationalizing cognitive impairments based on cognitive neuroscience have the potential to address these issues and facilitate the development of novel treatment strategies for CIAS. This includes more clearly elucidating pathophysiological mechanisms in both humans and animal models, identifying new treatment targets as well as establishing biomarkers for a better prediction of treatment responses.

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Allosteric Modulators of G Protein-Coupled Dopamine and Serotonin Receptors: A New Class of Atypical Antipsychotics

Cited by 20 publications

References 150 publications

Atypical Antipsychotics and Metabolic Syndrome: From Molecular Mechanisms to Clinical Differences

Atypical Antipsychotics and Metabolic Syndrome: From Molecular Mechanisms to Clinical Differences

Current Developments on the Role of α1-Adrenergic Receptors in Cognition, Cardioprotection, and Metabolism

Recent Developments in Treating Cognitive Impairment Associated with Schizophrenia

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