Molecular targets of atypical antipsychotics: From mechanism of action to clinical differences

Aringhieri, Stefano; Carli, Marco De; Kolachalam, Shivakumar; Verdesca, Valeria; Cini, Enrico; Rossi, Mario; McCormick, Peter J.; Corsini, Giovanni; Maggio, Roberto; Scarselli, Marco

doi:10.1016/j.pharmthera.2018.06.012

Cited by 158 publications

(128 citation statements)

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“…The drugs used in schizophrenia are divided into typical (first generation) and atypical antipsychotics, and among the latter, there are drugs classified as second and third generation. This classification groups together drugs rather heterogeneous in their clinical efficacy and tolerability as well as pharmacological profile [7]. However, it takes into account some fundamental mechanisms of action that are considered essential for the antipsychotic efficacy of currently approved antipsychotics.…”

Section: Introductionmentioning

confidence: 99%

N-(2-Hydroxyphenyl)-1-[3-(2-oxo-2,3-dihydro-1H- benzimidazol-1-yl)propyl]piperidine-4-Carboxamide (D2AAK4), a Multi-Target Ligand of Aminergic GPCRs, as a Potential Antipsychotic

et al. 2020

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N-(2-hydroxyphenyl)-1-[3-(2-oxo-2,3-dihydro-1H-benzimidazol -1-yl)propyl]piperidine-4-carboxamide (D2AAK4) is a multitarget ligand of aminergic G protein-coupled receptors (GPCRs) identified in structure-based virtual screening. Here we present detailed in vitro, in silico and in vivo investigations of this virtual hit. D2AAK4 has an atypical antipsychotic profile and low affinity to off-targets. It interacts with aminergic GPCRs, forming an electrostatic interaction between its protonatable nitrogen atom and the conserved Asp 3.32 of the receptors. At the dose of 100 mg/kg D2AAK4 decreases amphetamine-induced hyperactivity predictive of antipsychotic activity, improves memory consolidation in passive avoidance test and has anxiogenic properties in elevated plus maze test (EPM). Further optimization of the virtual hit D2AAK4 will be aimed to balance its multitarget profile and to obtain analogs with anxiolytic activity.

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Section: Introductionmentioning

confidence: 99%

N-(2-Hydroxyphenyl)-1-[3-(2-oxo-2,3-dihydro-1H- benzimidazol-1-yl)propyl]piperidine-4-Carboxamide (D2AAK4), a Multi-Target Ligand of Aminergic GPCRs, as a Potential Antipsychotic

et al. 2020

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“…This type of block is relevant especially for risperidone and eventually for olanzapine, given that they have high affinity for the D2 receptor and, at certain dosages, can have a receptor occupancy of 80% or above. On the contrary, clozapine and quetiapine never show a D2 receptor occupancy above 80% at their therapeutic concentrations which could explain why they never cause parkinsonism [48].…”

Section: Treatment Of Delirium Based On Toxicity And/or Side-effectsmentioning

confidence: 99%

“…In this case, the reduction of the general mobility or walking ability of the patient should be considered and suggested (Table 1). Moreover, drugs that produce a strong blockade of D2 receptors, such as risperidone or typical antipsychotics, should be avoided [48]. In this recent review [48] on this topic, the authors proposed a continuum spectrum of "atypia" that begins with risperidone (the least atypical) to clozapine (the most atypical), presenting all the other antipsychotics within the extremes of this spectrum.…”

Section: Treatment Of Delirium Based On Toxicity And/or Side-effectsmentioning

confidence: 99%

“…Moreover, drugs that produce a strong blockade of D2 receptors, such as risperidone or typical antipsychotics, should be avoided [48]. In this recent review [48] on this topic, the authors proposed a continuum spectrum of "atypia" that begins with risperidone (the least atypical) to clozapine (the most atypical), presenting all the other antipsychotics within the extremes of this spectrum. Clozapine is still considered the gold standard in refractory schizophrenia and in psychoses and hallucination present in Parkinson's disease, though it has been associated with adverse effects like agranulocytosis (at least 1.0% of users) and weight gain.…”

Section: Treatment Of Delirium Based On Toxicity And/or Side-effectsmentioning

confidence: 99%

“…In addition, new concepts related to GPCR function, such as biased agonism and receptor dimerization have recently been suggested which have added further complexity and intrigue over the mechanism of action of atypical antipsychotics. In fact, several studies have demonstrated how the activation of specific functions of the 5-HT2A receptor can be responsible to distinguish clozapine and other antipsychotics [48,54].…”

Section: Treatment Of Delirium Based On Toxicity And/or Side-effectsmentioning

confidence: 99%

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Treatment of Delirium in Older Persons: What We Should Not Do!

Lauretani

Bellelli

Pelà

et al. 2020

IJMS

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The presentation of common acute diseases in older age is often referred to as “atypical”. Frequently, the symptoms are neither single nor tissue related. In most cases, the onset of symptoms and diseases is the expression of a diminished reserve with a failure of the body system and imbalance of brain function. Delirium is one of the main devastating and prevalent atypical symptoms and could be considered as a geriatric syndrome. It encompasses an array of neuropsychiatric symptoms and represents a disarrangement of the cerebral function in response to one or more stressors. The most recent definition, reported in the DSM-V, depicts delirium as a clear disturbance in attention and awareness. The deficit is to be developed in a relatively short time period (usually hours or days). The attention disorder must be associated with another cognitive impairment in memory, orientation, language, visual-spatial or perception abilities. For the treatment, it is imperative to remove the potential causes of delirium before prescribing drugs. Even a non-pharmacological approach to reducing the precipitating causes should be identified and planned. When we are forced to approach the pharmacological treatment of hyperactive delirium in older persons, we should select highly cost-effective drugs. High attention should be devoted to the correct balance between improvement of psychiatric symptoms and occurrence of side effects. Clinicians should be guided in the correct choice of drugs following cluster symptoms presentation, excluding drugs that could potentially produce complications rather than advantages. In this brief point-of-view, we propose a novel pharmacological flow-chart of treatment in relation to the basic clusters of diseases of an older patient acutely admitted to the hospital and, in particular, we emphasize “What We Should Not Do!”, with the intention of avoiding possible side effects of drugs used.

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