Serotonergic Mechanisms as Targets for Existing and Novel Antipsychotics

Meltzer, Herbert Y.

doi:10.1007/978-3-642-25761-2_4

Cited by 88 publications

(74 citation statements)

References 220 publications

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“…A small decrease in dopamine levels in nucleus accumbens paralleled with slight increases in the metabolites HVA and DOPAC may indicate D 2 partial agonism, as previously reported in the striatum (Jordan et al, 2004). In the prefrontal cortex the regulation of neurotransmitter levels is different from nucleus accumbens; whereas selective D 2 antagonists alone have no effect, D 2 antagonism in conjunction with, e.g., 5-HT 2A antagonism or 5-HT 1A partial agonism, may increase extracellular dopamine and acetylcholine (Mørk et al, 2009;Meltzer, 1999Meltzer, , 2012. Accordingly, brexpiprazole would be expected to increase dopamine and acetylcholine in the prefrontal cortex as well, which did not happen despite slight increases in levels of HVA and DOPAC.…”

Section: Discussionmentioning

confidence: 62%

Brexpiprazole I: In Vitro and In Vivo Characterization of a Novel Serotonin-Dopamine Activity Modulator

Maeda

Sugino

Akazawa

et al. 2014

J Pharmacol Exp Ther

282

299

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Brexpiprazole piperazin-1-yl]butoxy}quinolin-2(1H)-one) is a novel drug candidate in clinical development for psychiatric disorders with high affinity for serotonin, dopamine, and noradrenaline receptors. In particular, it bound with high affinity (K i , 1 nM) to human serotonin 1A (h5-HT 1A )-, h5-HT 2A -, long form of human D 2 (hD 2L )-, ha 1B -, and ha 2C -adrenergic receptors. It displayed partial agonism at h5-HT 1A and hD 2 receptors in cloned receptor systems and potent antagonism of h5-HT 2A receptors and ha 1B/2C -adrenoceptors. Brexpiprazole also had affinity (K i , 5 nM) for hD 3 -, h5-HT 2B -, h5-HT 7 -, ha 1A -, and ha 1D -adrenergic receptors, moderate affinity for hH 1 (K i 5 19 nM), and low affinity for hM 1 receptors (K i . 1000 nM). Brexpiprazole potently bound to rat 5-HT 2A and D 2 receptors in vivo, and ex vivo binding studies further confirmed high 5-HT 1A receptor binding potency. Brexpiprazole inhibited DOI (2,5-dimethoxy-4-iodoamphetamine)-induced head twitches in rats, suggestive of 5-HT 2A antagonism. Furthermore, in vivo D 2 partial agonist activity of brexpiprazole was confirmed by its inhibitory effect on reserpine-induced DOPA accumulation in rats. In rat microdialysis studies, brexpiprazole slightly reduced extracellular dopamine in nucleus accumbens but not in prefrontal cortex, whereas moderate increases of the dopamine metabolites, homovanillic acid and DOPAC (3,4-dihydroxy-phenyl-acetic acid), in these areas also suggested in vivo D 2 partial agonist activity. In particular, based on a lower intrinsic activity at D 2 receptors and higher binding affinities for 5-HT 1A/2A receptors than aripiprazole, brexpiprazole would have a favorable antipsychotic potential without D 2 receptor agonistand antagonist-related adverse effects. In conclusion, brexpiprazole is a serotonin-dopamine activity modulator with a unique pharmacology, which may offer novel treatment options across a broad spectrum of central nervous system disorders.

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Section: Discussionmentioning

confidence: 62%

Brexpiprazole I: In Vitro and In Vivo Characterization of a Novel Serotonin-Dopamine Activity Modulator

Maeda

Sugino

Akazawa

et al. 2014

J Pharmacol Exp Ther

282

299

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“…Aripiprazole, an atypical APD, differs in that it achieves diminished D 2 receptor stimulation via partial DA D 2 agonism, thus reducing presynaptic DA release, and diminished activation of postsynaptic D 2 receptors because of its weak intrinsic agonist activity (22). The mechanism by which 5-HT 2A antagonism contributes to the antipsychotic actions and low EPS potential of these drugs has been discussed elsewhere (19,23).…”

Section: Pharmacology and Mechanism Of Action Of Atypical Antipsychotmentioning

confidence: 98%

Update on Typical and Atypical Antipsychotic Drugs

2013

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Antipsychotic drugs (APDs) are best classified as typical or atypical. The distinction is based solely on their ability to cause extrapyramidal side effects (EPS), including tardive dyskinesia (TD). The two classes differ in mechanism of action, with atypical APDs providing important modulation of serotonergic neurotransmission. TD increases the death rate and can be minimized by limiting use of typical APDs. Clozapine is unique among the atypical APDs in its efficacy for ameliorating psychosis in patients with treatment-resistant schizophrenia (TRS), for reduction of suicide, and for improving longevity. The typical and atypical APDs do not differ in improving psychopathology in non-TRS. The atypicals vary in metabolic side effects: some have little burden. Cognitive benefits of the atypical APDs may be superior for some domains of cognition and require less use of anticholinergic drugs, which impair memory, for treatment of EPS. Overall, choosing among the atypical APDs as first-line treatment represents the best course for schizophrenia and most likely other disorders for which APDs are used.

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“…Multiple lines of evidence suggest that antagonism of the dopamine D 2 receptor contributes to improvement of positive symptoms, whereas blockade of serotonin 5-HT 2A receptor is associated with improvement of negative symptoms as well as low risk of extrapyramidal side effects in schizophrenia (1,2). In addition to their action on these two key receptors, dopamine D 3 receptor has increasingly been considered as an attractive therapeutic target for schizophrenia (3,4).…”

Section: Introductionmentioning

confidence: 99%

Blonanserin extensively occupies rat dopamine D3 receptors at antipsychotic dose range

Baba

Enomoto

Horisawa

et al. 2015

Journal of Pharmacological Sciences

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Antagonism of the dopamine D3 receptor has been hypothesized to be beneficial for schizophrenia cognitive deficits, negative symptoms and extrapyramidal symptoms. However, recent animal and human studies have shown that most antipsychotics do not occupy D3 receptors in vivo, despite their considerable binding affinity for this receptor in vitro. In the present study, we investigated the D3 receptor binding of blonanserin, a dopamine D2/D3 and serotonin 5-HT2A receptors antagonist, in vitro and in vivo. Blonanserin showed the most potent binding affinity for human D3 receptors among the tested atypical antipsychotics (risperidone, olanzapine and aripiprazole). Our GTPγS-binding assay demonstrated that blonanserin acts as a potent full antagonist for human D3 receptors. All test-drugs exhibited antipsychotic-like efficacy in methamphetamine-induced hyperactivity in rats. Treatment with blonanserin at its effective dose blocked the binding of [(3)H]-(+)-PHNO, a D2/D3 receptor radiotracer, both in the D2 receptor-rich region (striatum) and the D3 receptor-rich region (cerebellum lobes 9 and 10). On the other hand, the occupancies of other test-drugs for D3 receptors were relatively low. In conclusion, we have shown that blonanserin, but not other tested antipsychotics, extensively occupies D3 receptors in vivo in rats.

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Serotonergic Mechanisms as Targets for Existing and Novel Antipsychotics

Cited by 88 publications

References 220 publications

Brexpiprazole I: In Vitro and In Vivo Characterization of a Novel Serotonin-Dopamine Activity Modulator

Brexpiprazole I: In Vitro and In Vivo Characterization of a Novel Serotonin-Dopamine Activity Modulator

Update on Typical and Atypical Antipsychotic Drugs

Blonanserin extensively occupies rat dopamine D3 receptors at antipsychotic dose range

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