BACKGROUNDDopamine receptor antagonists have recently been identified as potential anti-cancer agents in combination with radiation, and a first drug of this class is in clinical trials against pediatric glioma. Radiotherapy causes cognitive impairment primarily by eliminating neural stem/progenitor cells and subsequent loss of neurogenesis, along with inducing inflammation, vascular damage, and synaptic alterations. Here, we tested the combined effects of dopamine receptor antagonists and radiation on neural stem/progenitor cells.METHODSUsing transgenic mice that report the presence of neural stem/progenitor cells through Nestin promoter-driven expression of EGFP, the effects of dopamine receptor antagonists alone or in combination with radiation on neural stem/progenitor cells were assessed in sphere-formation assays, extreme limiting dilution assays, flow cytometry and real-time PCR in vitro and in vivo in both sexes.RESULTSWe report that hydroxyzine and trifluoperazine exhibited sex-dependent effects on murine newborn neural stem/progenitor cells in vitro. In contrast, amisulpride, nemonapride, and quetiapine, when combined with radiation, significantly increased the number of neural stem/progenitor cells in both sexes. In vivo, trifluoperazine showed sex-dependent effects on adult neural stem/progenitor cells, while amisulpride demonstrated significant effects in both sexes. Further, amisulpride increased sphere forming capacity and stem cell frequency in both sexes when compared to controls.CONCLUSIONWe conclude that a therapeutic window for dopamine receptor antagonists in combination with radiation potentially exists, making it a novel combination therapy against glioblastoma. Normal tissue toxicity following this treatment scheme likely differs depending on age and sex and should be taken into consideration when designing clinical trials.

01 Apr 2023·Pharmacological Reports

Agonistic properties of a series of psychotropic drugs at 5-HT1A receptors in rat and human brain membranes determined by [35S]GTPγS binding assay

Article

Author: Odagaki, Yuji ; García-Sevilla, Jesús A ; Mikami, Masaki ; Borroto-Escuela, Dasiel Oscar ; Fuxe, Kjell ; Meana, J Javier ; Callado, Luis F ; Kinoshita, Masakazu

BACKGROUNDMany psychoactive compounds have been developed to have more beneficial clinical efficacy than conventional drugs by adding agonistic action at 5-HT_1A receptors. The aim of the present study was to evaluate several psychotropic drugs that had been reported to behave as an agonist at 5-HT_1A receptor (aripiprazole, brexpiprazole, asenapine, lurasidone, and vortioxetine) in both rat and postmortem human brain membranes.METHODSThe [³⁵S]GTPγS binding assay for G_i/o proteins coupled with 5-HT_1A receptors was performed in rat brain membranes and postmortem human brain membranes.RESULTSThe specific binding was stimulated by brexpiprazole in rat hippocampus, human hippocampus, and human prefrontal cortex. Aripiprazole also behaved as an agonist in the same brain regions. Interestingly, its potency was much higher in rat hippocampal membranes than in human brain membranes, indicating the possibility of species differences. Although vortioxetine was an efficacious stimulator at high concentrations, its potency was undeterminable because of a lack of saturability. In addition to 5-HT_1A receptor agonism, involvement of other components, e.g., 5-HT_1B receptor agonism, was speculated by the biphasic inhibitory effects of the selective 5-HT_1A receptor neutral antagonist. Negligible stimulatory effects were obtained as to lurasidone and asenapine.CONCLUSIONSOur previous studies have raised the concept of a psychoactive drug group with a common pharmacological mechanism of action, i.e., 5-HT_1A receptor agonism, consisting of perospirone, aripiprazole, ziprasidone, clozapine, quetiapine, nemonapride, and trazodone. The present study demonstrates the data indicating that brexpiprazole and probably vortioxetine are included in this drug group. Lurasidone and asenapine are excluded from this group.

01 Jun 2022·European Journal of PharmacologyQ3 · MEDICINE

Interaction of the preferential D3 agonist (+)PHNO with dopamine D3-D2 receptor heterodimers and diverse classes of monoamine receptor: relevance for PET imaging

Q3 · MEDICINE

Article

Author: Scarselli, Marco ; Carli, Marco ; di Cara, Benjamin ; Millan, Mark J ; Marampon, Francesco ; Aloisi, Gabriella ; Petragnano, Francesco ; Kolachalam, Shivakumar ; Maggio, Roberto ; Mannoury la Cour, Clotilde ; Rossi, Mario ; Fasciani, Irene

(+)-4-Propyl-9-hydroxynaphthoxazine ((+)PHNO) is a high affinity, preferential dopamine D₃ versus D₂ agonist employed in view of its high specificity and excellent signal-to-noise ratio as a radiotracer for positron emission tomography (PET) imaging. Surprisingly, its profile at other classes of monoamine receptor remains undocumented. In addition to hD₃ and hD_2L receptors, (+)PHNO revealed high affinity at hD_4.4 but not hD₁ or hD₅ receptors. It also revealed significant affinity for several other G protein-coupled monoaminergic receptors, in particular h5-HT_1A and h5-HT₇. (+)PHNO behaved as a full agonist at hD_4.4 and h5-HT_1A receptors with potencies comparable to its actions at hD₃ and hD_2L receptors, and with less potency at 5-HT₇ receptors. In binding assays with membranes derived from cells co-expressing hD₃ and hD_2L receptors and labeled with [³H]Nemonapride or [³H]Spiperone, the proportion of high affinity binding sites recognized by (+)PHNO was higher than an equivalent mixture of membranes from cells expressing hD₃or hD_2L receptors, suggesting that (+)PHNO promotes formation of hD₃-hD_2L heterodimers. Further, in cells co-expressing hD₃ and hD_2L receptors, (+)PHNO showed higher efficacy for inhibiting forskolin stimulated adenylyl cyclase and inducing adenylyl cyclase super-sensitization than in cells transfected with only hD_2L receptors. In conclusion, (+)PHNO is a potent agonist at hD₄.₄, h5-HT_1A and h5-HT₇ as well as hD₃ and hD_2L receptors, and it potently activates dopamine hD₃-hD_2L heterodimers. These interactions should be considered when interpreting PET studies with [¹¹C](+)PHNO and may be relevant to its functional and potential clinical properties in Parkinson's disease and other disorders.

100 Deals associated with Nemonapride

External Link

KEGG	Wiki	ATC	Drug Bank
D01468	Nemonapride	N05A	-

R&D Status

10 top approved records.

to view more data

Indication	Country/Location	Organization	Date
Schizophrenia	JP	LTL Pharma Co., Ltd.	29 Mar 1991

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis