Last update 01 Nov 2024

GABAB receptor x nAChRα9&α10

Last update 01 Nov 2024

Basic Info

Related Targets

GABAB receptornAChRα9&α10

Drugs associated with GABAB receptor x nAChRα9&α10

GeX-2

Target

GABAB receptor x nAChRα9&α10

Mechanism

GABAB receptor antagonists [+1]

Active Org.

Ocean University of China

Originator Org.

Ocean University of China

Active Indication

Pain

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with GABAB receptor x nAChRα9&α10

100 Translational Medicine associated with GABAB receptor x nAChRα9&α10

0 Patents (Medical) associated with GABAB receptor x nAChRα9&α10

Literatures (Medical) associated with GABAB receptor x nAChRα9&α10

24 Oct 2024·Journal of Medicinal Chemistry

N-Terminal Capping of the αO-Conotoxin Analogue GeX-2 Improves the Serum Stability and Selectivity toward the Human α9α10 Nicotinic Acetylcholine Receptor

Article

Author: Li, Xiao ; Jiang, Tao ; Zhou, Shenglu ; Wang, Shoushi ; Li, Tianmiao ; Tae, Han-Shen ; Cai, Wenqing ; Yu, Rilei ; Adams, David J.

α9α10 nicotinic acetylcholine receptors (nAChRs) are a promising nonopioid analgesic target, with α9α10 nAChR antagonists showing efficacy against chemotherapy-induced hyperalgesia and allodynia. GeX-2, a potent analgesic conotoxin antagonist of α9α10 nAChRs, has limited serum stability. This study improved GeX-2 stability by capping its N-terminal with fatty acids or polyethylene glycol chains, which enhanced its serum stability but eliminated activity at G protein-coupled γ-aminobutyric acid type B (GABA_B) receptor-coupled Ca_V2.2 channels while preserving activity at α9α10 nAChRs. In vivo, α9α10 nAChRs antagonism alone did not alleviate neuropathic pain, highlighting the importance of GABA_B receptor-coupled Ca_V2.2 channels in GeX-2's antinociceptive effects in the chronic constriction injury rat model. The GeX-2 analogue, with an N-terminal methyl group, showed improved activity and selectivity for α9α10 nAChRs, increased serum half-life, and strong analgesic effects in oxaliplatin-induced cold allodynia models. AlphaFold3 and molecular dynamics simulations provided insights into the binding modes and the effects of N-terminal capping, which informed future peptide therapeutic developments.

25 Jan 2024·Journal of Medicinal ChemistryQ1 · MEDICINE

Dual Antagonism of α9α10 nAChR and GABA_B Receptor-Coupled Ca_V2.2 Channels by an Analgesic αO-Conotoxin Analogue

Q1 · MEDICINE

Article

Author: Li, Xiao ; Tae, Han-Shen ; Huang, Linhong ; Jiang, Tao ; Yousuf, Arsalan ; Zhang, Jinghui ; Adams, David J. ; Yu, Rilei ; Chen, Shen

Pain severely affects the physical and mental health of patients. The need to develop nonopioid analgesic drugs to meet medical demands is urgent. In this study, we designed a truncated analogue of αO-conotoxin, named GeX-2, based on disulfide-bond deletion and sequence truncation. GeX-2 retained the potency of its parent peptide at the human α9α10 nAChR and exhibited potent inhibitory activity at Ca_V2.2 channels via activation of the GABA_B receptor (GABA_BR). Importantly, GeX-2 significantly alleviated pain in the rat model of chronic constriction injury. The dual inhibition of GeX-2 at both α9α10 nAChRs and Ca_V2.2 channels is speculated to synergistically mediate the potent analgesic effects. Results from site-directed mutagenesis assay and computational modeling suggest that GeX-2 preferentially interacts with the α10(+)α10(-) binding site of α9α10 nAChR and favorably binds to the top region of the GABA_BR2 subunit. The study offers vital insights into the molecular action mechanism of GeX-2, demonstrating its potential as a novel nonopioid analgesic.

01 Jan 2022·Journal of Neurochemistry

ɑO‐Conotoxin GeXIVA isomers modulate N‐type calcium (Ca_V2.2) channels and inwardly‐rectifying potassium (GIRK) channels via GABA_B receptor activation

Article

Author: Wu, Xiaosa ; Sadeghi, Mahsa ; Craik, David J. ; Bony, Anuja R. ; Huang, Yen‐Hua ; Yousuf, Arsalan ; Adams, David J.

AbstractαO‐Conotoxin GeXIVA is a 28 amino acid peptide derived from the venom of the marine snail Conus generalis. The presence of four cysteine residues in the structure of GeXIVA allows it to have three different disulfide isomers, that is, the globular, ribbon or bead isomer. All three isomers are active at α9α10 nicotinic acetylcholine receptors, with the bead isomer, GeXIVA[1,2], being the most potent and exhibiting analgesic activity in animal models of neuropathic pain. The original report of GeXIVA activity failed to observe any effect of the isomers on high voltage‐activated (HVA) calcium channel currents in rat dorsal root ganglion (DRG) neurons. In this study, we report, for the first time, the activity of globular GeXIVA[1,3] at G protein‐coupled GABAB receptors (GABABR) inhibiting HVA N‐type calcium (Cav2.2) channels and reducing membrane excitability in mouse DRG neurons. The inhibition of HVA Ba2+ currents and neuroexcitability by GeXIVA[1,3] was partially reversed by the selective GABABR antagonist CGP 55845. In transfected HEK293T cells co‐expressing human GABABR1 and R2 subunits and Cav2.2 channels, both GeXIVA[1,3] and GeXIVA[1,4] inhibited depolarization‐activated Ba2+ currents mediated by Cav2.2 channels, whereas GeXIVA[1,2] had no effect. The effects of three cyclized GeXIVA[1,4] ribbon isomers were also tested, with cGeXIVA GAG being the most potent at human GABABR‐coupled Cav2.2 channels. Interestingly, globular GeXIVA[1,3] also reversibly potentiated inwardly‐rectifying K+ currents mediated by human GIRK1/2 channels co‐expressed with GABABR in HEK293T cells. This study highlights GABABR as a potentially important receptor target for the activity of αO‐conotoxin GeXIVA to mediate analgesia.

image

Analysis

Perform a panoramic analysis of this field.

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