GABAA receptor antagonists(Gamma-aminobutyric acid A receptor antagonists), GABAB receptor antagonists(Gamma-Aminobutyric Acid B Receptor antagonists)

Therapeutic Areas

Nervous System Diseases

Active Indication

Epilepsy

Inactive Indication-

Originator Organization

Ciba-Geigy AG

Active Organization

Institute of Physics AS CR

Inactive Organization

Ciba-Geigy AG

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure

Molecular FormulaC10H22NO2P

InChIKeyXOESDNIUAWGCLU-UHFFFAOYSA-N

CAS Registry123691-14-5

100 Clinical Results associated with CGP-46381

100 Translational Medicine associated with CGP-46381

100 Patents (Medical) associated with CGP-46381

Literatures (Medical) associated with CGP-46381

06 Sep 2023·International journal of molecular sciences

GABBR2 as a Downstream Effector of the Androgen Receptor Induces Cisplatin Resistance in Bladder Cancer.

Article

Author: Miyamoto, Hiroshi ; Teramoto, Yuki ; Yasui, Masato ; Elahi Najafi, Mohammad Amin ; Jiang, Guiyang ; Tatenuma, Tomoyuki

The precise molecular mechanisms responsible for resistance to cisplatin-based chemotherapy in patients with bladder cancer remain elusive, while we have indicated that androgen receptor (AR) activity in urothelial cancer is associated with its sensitivity. Our DNA microarray analysis in control vs. AR-knockdown bladder cancer sublines suggested that the expression of a GABA B receptor GABBR2 and AR was correlated. The present study aimed to determine the functional role of GABBR2 in modulating cisplatin sensitivity in bladder cancer. AR knockdown and dihydrotestosterone treatment considerably reduced and induced, respectively, GABBR2 expression, and the effect of dihydrotestosterone was at least partially restored by an antiandrogen hydroxyflutamide. A chromatin immunoprecipitation assay further revealed the binding of AR to the promoter region of GABBR2 in bladder cancer cells. Meanwhile, GABBR2 expression was significantly elevated in a cisplatin-resistant bladder cancer subline, compared with control cells. In AR-positive bladder cancer cells, knockdown of GABBR2 or treatment with a selective GABA B receptor antagonist, CGP46381, considerably enhanced the cytotoxic activity of cisplatin. However, no additional effect of CGP46381 on cisplatin-induced growth suppression was seen in GABBR2-knockdown cells. Moreover, in the absence of cisplatin, CGP46381 treatment and GABBR2 knockdown showed no significant changes in cell proliferation or migration. These findings suggest that GABBR2 represents a key downstream effector of AR signaling in inducing resistance to cisplatin treatment. Accordingly, inhibition of GABBR2 has the potential of being a means of chemosensitization, especially in patients with AR/GABBR2-positive bladder cancer.

17 Nov 2022·Oxidative Medicine and Cellular Longevity

BHF177 Suppresses Diabetic Neuropathic Pain by Blocking PKC/CaMKII/ERK1/2/CREB Signaling Pathway through Activating GABAB Receptor

Article

Author: Niu, Yao ; Liu, Boyu ; Zhao, Jiapeng ; Jiang, Hongbo ; Guan, Fengxi

The gamma-aminobutyric acid type B (GABAB) receptor may participate in the development of diabetic neuropathic pain (DNP). BHF177 serves as a positive allosteric modulator of the GABAB receptor. In the current study, we sought to study the role of the BHF177-GABAB receptor in DNP and its underlying mechanism. Streptozotocin was adopted to induce a rat model of DNP, followed by determination of the paw withdrawal threshold (PWT), paw withdrawal latency (PWL), and glucose level. The effect of BHF177 on DNP by regulating the GABAB receptor in vivo was determined by the injection of BHF177 and/or CGP46381 (a GABAB receptor antagonist) into rat models of DNP. Hippocampal neuronal cells were isolated and cultured, and the neurons and DNP model rats were treated with activators of PKC (PMA), CaMKII (CaCl2), or ERK1/2 (EGF) to study the role of GABAB receptors in DNP via regulation of the NR2B-PKC-CaMKII-ERK-CREB pathway. BHF177 suppressed DNP symptoms by activating the GABAB receptors, as evidenced by increased PWT and PWL of DNP rats and the increased number of neurons expressing the GABAB receptor, but this effect was reversed by CGP46381 treatment. BHF177 treatment markedly repressed PKC, CaMKII, p-ERK1/2, and p-CREB expressions in the rat DNP model, but these suppressive effects were abrogated by treatments with PMA, CaCl2, or EGF treatment, respectively. To sum up, BHF177 suppresses DNP symptoms by blocking the PKC/CaMKII/ERK1/2/CREB signaling pathway to activate the GABAB receptors.

01 Nov 2022·Cell Biology International

Effects of GABA_B receptor positive allosteric modulator BHF177 and IRS‐1 on apoptosis of hippocampal neurons in rats with refractory epilepsy via the PI3K/Akt pathway

Article

Author: Zhang, Yizhi ; Nan, Shanji ; Wang, Peng ; Fan, Jia

AbstractThe present study was conducted to determine the effects of the γ‐aminobutyric acid B (GABAB) receptor positive allosteric modulator BHF177 on refractory epilepsy (RE). An RE rat model was initially established via treatment with lithium‐pilocarpine. The RE rats were then treated with BHF177 or the GABAB receptor antagonist CGP46381, followed by recording of their seizure rate and assessment of their spatial learning in the Morris water maze test. Treatment of BHF177 reduced the seizure intensity, whereas this effect was revered upoj treatment with CGP46381. Immunohistochemistry revealed that BHF177 treatment diminished P‐glycoprotein (P‐gp) expression in the hippocampal tissues of RE rats. Next, we found that BHF177 activated GABAB receptor, resulting in upregulated expression of insulin receptor substrate 1 (IRS‐1) and PI3K, as well as antiapoptotic factors (Bcl‐2 and mTOR), along with suppression of the apoptosis factors Bax and cleaved caspase‐3 in the hippocampal tissues. Further, activation of GABAB receptors by BHF177 alleviated the inflammatory response in hippocampal tissues of RE rats, as evidenced by reduced VCAM‐1, ICAM‐1, and tumor necrosis factor‐α levels. Next, we treated primary cultured rat hippocampal neurons with BHF177 and the IRS‐1 selective inhibitor NT157. BHF177 inhibited hippocampal apoptosis in rat hippocampal neurons by regulating the IRS‐1/PI3K/Akt axis through crosstalk between GABAB and insulin‐like growth factor‐1 receptors. Collectively, our findings indicate that the BHF177 inhibited neuron apoptosis, thus protecting against RE through the IRS‐1/PI3K/Akt axis, which may present a new therapeutic channel for RE.

100 Deals associated with CGP-46381

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Epilepsy	Preclinical	CZ	Institute of Physics AS CR	29 Aug 2011

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


No Data

CGP-46381

Overview

Basic Info

Structure

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation