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

@article{Maeda2014BrexpiprazoleII,
  title={Brexpiprazole I: In Vitro and In Vivo Characterization of a Novel Serotonin-Dopamine Activity Modulator},
  author={Kenji Maeda and Haruhiko Sugino and Hitomi Akazawa and Naoki Amada and Jun Shimada and Takashi Futamura and Hiroshi Yamashita and Nobuaki Ito and Robert Mcquade and Arne M{\o}rk and Alan L Pehrson and Morten Hentzer and Vibeke Nielsen and Christoffer Bundgaard and J{\o}rn Arnt and Tine Bryan Stensb{\o}l and Tetsuro Kikuchi},
  journal={The Journal of Pharmacology and Experimental Therapeutics},
  year={2014},
  volume={350},
  pages={589 - 604}
}
Brexpiprazole (OPC-34712, 7-{4-[4-(1-benzothiophen-4-yl)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 (Ki < 1 nM) to human serotonin 1A (h5-HT1A)-, h5-HT2A-, long form of human D2 (hD2L)-, hα1B-, and hα2C-adrenergic receptors. It displayed partial agonism at h5-HT1A and hD2 receptors in cloned receptor systems… 
Brexpiprazole II: Antipsychotic-Like and Procognitive Effects of a Novel Serotonin-Dopamine Activity Modulator
TLDR
The results indicate that brexpiprazole has antipsychotic-like activity and robust efficacy in relevant models of cognitive impairment associated with schizophrenia, and the pharmacologic profile of brexpIPrazole is proposed to be based on its balanced effects on 5-HT1A, D2, and 5- HT2A receptors, with possible modulating activity through additional monoamine receptors.
Acute Effects of Brexpiprazole on Serotonin, Dopamine, and Norepinephrine Systems: An In Vivo Electrophysiologic Characterization
TLDR
In conclusion, the in vivo action of brexpiprazole on monoamine targets relevant in the treatment of depression and schizophrenia is assessed and α1- and α2-adrenergic receptors are evaluated.
Involvement of 5-HT1A and 5-HT2A Receptors but Not α2-Adrenoceptors in the Acute Electrophysiological Effects of Cariprazine in the Rat Brain In Vivo
TLDR
Results indicate that, in vivo, cariprazine acted as a 5-HT1A autoreceptor agonist in the DRN, a5-HT2A receptor antagonist in modulating the firing activity of LC NE neurons, and a full agonist at 5- HT1A receptors mediating the electrophysiological effect of 5-hydroxytryptamine on pyramidal neurons.
Investigating the Potential Role of Serotonin-2B Receptor Antagonism in the Neuronal Actions of Adjunctive Aripiprazole
TLDR
5-HT2B receptor blockade rescues an SSRI-mediated decrease in DA firing activity and increases mPFC pyramidal neuron firing and bursting activity mediated by aripiprazole and in combination with escitalopram may be, at least partly, moderated by 5- HT2B receptors expressed in this brain area.
In Vitro and In Vivo Characterization of PCC0104005, a Novel Modulator of Serotonin-Dopamine Activity, as an Atypical Antipsychotic Drug
TLDR
PCC0104005 has unique affinities for dopamine receptors and serotonin receptors, which may lead to clinical advantages, as well as fewer adverse reactions.
In vitro evaluations for pharmacokinetic drug-drug interactions of a novel serotonin-dopamine activity modulator, brexpiprazole
TLDR
In vitro data suggest that brexpiprazole is unlikely to cause clinically relevant drug interactions resulting from the effects on CYPs or transporters mediating the absorption, metabolism, and/or disposition of co-administered drugs.
Involvement of presynaptic 5-HT1A receptors in the low propensity of brexpiprazole to induce extrapyramidal side effects in rats
...
...

References

SHOWING 1-10 OF 114 REFERENCES
Brexpiprazole II: Antipsychotic-Like and Procognitive Effects of a Novel Serotonin-Dopamine Activity Modulator
TLDR
The results indicate that brexpiprazole has antipsychotic-like activity and robust efficacy in relevant models of cognitive impairment associated with schizophrenia, and the pharmacologic profile of brexpIPrazole is proposed to be based on its balanced effects on 5-HT1A, D2, and 5- HT2A receptors, with possible modulating activity through additional monoamine receptors.
Urapidil and some analogues with hypotensive properties show high affinities for 5-hydroxytryptamine (5-HT) binding sites of the 5-HT1A subtype and for α1-adrenoceptor binding sites
TLDR
5-methyl-urapidil is one of the most potent ligands at 5-HT1A recognition sites known to date and is relevant to the hypotensive properties of these compounds.
Aripiprazole's low intrinsic activities at human dopamine D2L and D2S receptors render it a unique antipsychotic.
(1-(2,5-dimethoxy-4 iodophenyl)-2-aminopropane)-induced head-twitches in the rat are mediated by 5-hydroxytryptamine (5-HT) 2A receptors: modulation by novel 5-HT2A/2C antagonists, D1 antagonists and 5-HT1A agonists.
TLDR
It is demonstrated that 5-HT2A receptors mediate HTW in rats and that both D1 and D2 receptors as well as (postsynaptic) 5- HT1A receptors play a role in their expression.
Aripiprazole, A Novel Atypical Antipsychotic Drug with a Unique and Robust Pharmacology
TLDR
The results support the hypothesis that the unique actions of aripiprazole in humans are likely a combination of ‘functionally selective’ activation of D2 (and possibly D3)-dopamine receptors, coupled with important interactions with selected other biogenic amine receptors—particularly 5-HT receptor subtypes (5-HT1A, 5- HT2A).
Differential effects of aripiprazole on D(2), 5-HT(2), and 5-HT(1A) receptor occupancy in patients with schizophrenia: a triple tracer PET study.
TLDR
Aripiprazole exhibits a unique occupancy profile as compared with other conventional and atypical antipsychotics, and the threshold for response appears to be higher than 60%, extrapyramidal side effects appear to be uncommon even at occupancies that exceed the conventional extrapYramidal Side effects threshold of 80%, and 5-HT(2) occupancy is lower than D( 2) occupancy.
Serotonergic mechanisms as targets for existing and novel antipsychotics.
  • H. Meltzer
  • Psychology, Biology
    Handbook of experimental pharmacology
  • 2012
TLDR
An update of current preclinical and clinical evidence for the role of these five 5-HT receptors in the actions of current APDs and for the development of novel psychotropic drugs is provided.
Aripiprazole, a Novel Antipsychotic, Is a High-Affinity Partial Agonist at Human Dopamine D2 Receptors
TLDR
These results, together with previous studies demonstrating partial agonist activity at serotonin 5-hydroxytryptamine (5-HT)1A receptors and antagonist activity at 5-HT2A receptors, support the identification of aripiprazole as a dopamine-serotonin system stabilizer.
...
...