In vitro and in vivo characterization of PA01, a novel promising triple reuptake inhibitor

Hou, Jian; Xing, Yanli; Zuo, Daiying; Wu, Yuankui; Tian, Jingwei; Meng, Qingguo; Yang, Mina

doi:10.1016/j.physbeh.2014.10.007

Cited by 5 publications

(3 citation statements)

References 42 publications

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“…Hou et al have disclosed PA01 ( 219 ), the benzoate ester of the SNRI 20 (Figure ). Compound 219 showed a dose-dependent increase of mobility time in both the rat FST and mouse TST models with higher efficacy than 20 while showing no stimulatory effect on spontaneous locomotor activity. The anti-immobility effect of 219 was significantly reversed by pretreatment of the mice with 4-chlorophenylalanine, an inhibitor of 5-HT synthesis, the D 1 antagonist SCH23390 ( 220 ), and the D 2 antagonist sulpiride ( 221 ) (Figure ).…”

Section: Discovery and Development Of Trismentioning

confidence: 95%

Triple Reuptake Inhibitors as Potential Therapeutics for Depression and Other Disorders: Design Paradigm and Developmental Challenges

Subbaiah

2017

J. Med. Chem.

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Although first-line antidepressants offer therapeutic benefit, about 35% of depressed patients are not adequately treated, creating a large unmet medical need. These medicines mostly enhance the synaptic levels of serotonin and/or norepinephrine. Evidence from preclinical and clinical studies implicate dopamine hypofunction in the pathophysiology of depression. Triple reuptake inhibitors (TRIs), which elevate dopamine in addition to serotonin and norepinephrine, may demonstrate greater efficacy, with the reversal of anhedonia and improved tolerability. Medicinal chemistry efforts have resulted in more than 10 clinical candidates, although clinical candidates have failed to demonstrate superior efficacy compared to placebo or existing antidepressants. Hence, the successful development of future TRIs for depression will demand strong translational evidence, an optimal dosing regimen, and better tolerability. TRIs also hold therapeutic potential for other indications, with four candidates under clinical development for attention deficit hyperactivity disorder, binge eating disorder, cocaine addiction, obesity, and type 2 diabetes. Clinical studies have indicated a lower abuse potential for TRIs than psychostimulants.

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Section: Discovery and Development Of Trismentioning

confidence: 95%

Triple Reuptake Inhibitors as Potential Therapeutics for Depression and Other Disorders: Design Paradigm and Developmental Challenges

Subbaiah

2017

J. Med. Chem.

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“…Sodium benzoate was also a metabolite of cinnamon [ 49 ]. Some other benzoate compounds are promising antidepressant candidates, such as 4-[1-[1-(benzoyloxy)cyclohexyl]-2-(dimethylamino)ethyl]-phenyl benzoate [ 50 ], 4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)-ethyl]-phenyl benzoate hydrochloride [ 51 ], and potassium 2-(1-hydroxypentyl)-benzoate [ 52 ]. As described above in the introduction, the degradation by gut microbiota enzymes may be one of the main reasons for the low bioavailability of paeoniflorin, and the pharmacological effect of paeoniflorin may be produced by the resultant metabolites.…”

Section: Discussionmentioning

confidence: 99%

The Study of a Novel Paeoniflorin-Converting Enzyme from Cunninghamella blakesleeana

Pei

Cao

et al. 2023

Molecules

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Paeoniflorin is a glycoside compound found in Paeonia lactiflora Pall that is used in traditional herbal medicine and shows various protective effects on the cardio-cerebral vascular system. It has been reported that the pharmacological effects of paeoniflorin might be generated by its metabolites. However, the bioavailability of paeoniflorin by oral administration is low, which greatly limits its clinical application. In this paper, a paeoniflorin-converting enzyme gene (G6046, GenBank accession numbers: OP856858) from Cunninghamella blakesleeana (AS 3.970) was identified by comparative analysis between MS analysis and transcriptomics. The expression, purification, enzyme activity, and structure of the conversion products produced by this paeoniflorin-converting enzyme were studied. The optimal conditions for the enzymatic activity were found to be pH 9, 45 °C, resulting in a specific enzyme activity of 14.56 U/mg. The products were separated and purified by high-performance counter-current chromatography (HPCCC). Two main components were isolated and identified, 2-amino-2-p-hydroxymethyl-methyl alcohol-benzoate (tirs-benzoate) and 1-benzoyloxy-2,3-propanediol (1-benzoyloxypropane-2,3-diol), via UPLC-Q-TOF-MS and NMR. Additionally, paeoniflorin demonstrated the ability to metabolize into benzoic acid via G6046 enzyme, which might exert antidepressant effects through the blood–brain barrier into the brain.

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“…Then, all animals were intraperitoneally injected with 0.9% saline or 5-HTP (320 mg/kg) 40 min before the test. The number of head twitches was recorded during a period of 40–70 min after intraperitoneal injection 37 .…”

Section: Methodsmentioning

confidence: 99%

In Vitro and In Vivo Characterization of PCC0104005, a Novel Modulator of Serotonin-Dopamine Activity, as an Atypical Antipsychotic Drug

Zhu

Wang

et al. 2018

Sci Rep

Self Cite

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PCC0104005 is a novel drug candidate for treating schizophrenia that displays high affinity for serotonin, dopamine, and noradrenaline receptors, including partial agonism at dopamine D2, D3, D4, serotonin 5-HT1A, and 5-HT2A receptors and antagonism at 5-HT2B, 5-HT6, and 5-HT7 receptors. PCC0104005 blocks MK-801-induced hyperactivity in rats, consistent with the reduction in dopamine D2 receptor stimulation and increased dopamine release in the medial prefrontal cortex. PCC0104005 inhibits 5-HTP-induced head twitches in rats, due to its moderate affinity for human 5-HT2A receptors (Ki = 5.1 nM). PCC0104005 significantly reduced the escape latency of rats and improved the MK-801-induced memory impairment. In the object recognition experiment, PCC0104005 significantly improved the recognition disorder induced by MK-801. PCC0104005 did not significantly increase the plasma prolactin level, which is thought to be related to the preferential affinity of PCC0104005 for dopamine D2 receptors compared with 5-HT1A receptors, as well as the relative antagonistic activity toward the D2 receptor. Due to its 5-HT1A agonism, PCC0104005 does not produce catalepsy in mice, a behaviour predictive of the occurrence of extra-pyramidal syndrome (EPS) in humans. PCC0104005 has unique affinities for dopamine receptors and serotonin receptors, which may lead to clinical advantages, as well as fewer adverse reactions.

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In vitro and in vivo characterization of PA01, a novel promising triple reuptake inhibitor

Cited by 5 publications

References 42 publications

Triple Reuptake Inhibitors as Potential Therapeutics for Depression and Other Disorders: Design Paradigm and Developmental Challenges

Triple Reuptake Inhibitors as Potential Therapeutics for Depression and Other Disorders: Design Paradigm and Developmental Challenges

The Study of a Novel Paeoniflorin-Converting Enzyme from Cunninghamella blakesleeana

In Vitro and In Vivo Characterization of PCC0104005, a Novel Modulator of Serotonin-Dopamine Activity, as an Atypical Antipsychotic Drug

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