Last update 01 Nov 2024

ASIC3 x ASIC1

Last update 01 Nov 2024

Basic Info

Related Targets

ASIC3ASIC1

Drugs associated with ASIC3 x ASIC1

Triol

Target

ASIC1 x ASIC3

Mechanism

ASIC1 antagonists [+1]

Active Org.

Morehouse School of Medicine

Originator Org.-

Active Indication

ischemic brain injury [+1]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with ASIC3 x ASIC1

100 Translational Medicine associated with ASIC3 x ASIC1

0 Patents (Medical) associated with ASIC3 x ASIC1

Literatures (Medical) associated with ASIC3 x ASIC1

01 Jun 2024·Stroke

Cholestane-3β,5α,6β-Triol Inhibits Acid-Sensing Ion Channels and Reduces Acidosis-Mediated Ischemic Brain Injury

Article

Author: Xiong, Zhi-Gang ; Leng, Tiandong ; Yang, Tao ; Sun, Huawei ; Simon, Roger

BACKGROUND:Activation of the acid-sensing ion channels (ASICs) by tissue acidosis, a common feature of brain ischemia, contributes to ischemic brain injury, while blockade of ASICs results in protection. Cholestane-3β,5α,6β-triol (Triol), a major cholesterol metabolite, has been demonstrated as an endogenous neuroprotectant; however, the mechanism underlying its neuroprotective activity remains elusive. In this study, we tested the hypothesis that inhibition of ASICs is a potential mechanism.METHODS:The whole-cell patch-clamp technique was used to examine the effect of Triol on ASICs heterogeneously expressed in Chinese hamster ovary cells and ASICs endogenously expressed in primary cultured mouse cortical neurons. Acid-induced injury of cultured mouse cortical neurons and middle cerebral artery occlusion–induced ischemic brain injury in wild-type and ASIC1 and ASIC2 knockout mice were studied to examine the protective effect of Triol.RESULTS:Triol inhibits ASICs in a subunit-dependent manner. In Chinese hamster ovary cells, it inhibits homomeric ASIC1a and ASIC3 without affecting ASIC1β and ASIC2a. In cultured mouse cortical neurons, it inhibits homomeric ASIC1a and heteromeric ASIC1a–containing channels. The inhibition is use-dependent but voltage- and pH-independent. Structure-activity relationship analysis suggests that hydroxyls at the 5 and 6 positions of the A/B ring are critical functional groups. Triol alleviates acidosis-mediated injury of cultured mouse cortical neurons and protects against middle cerebral artery occlusion–induced brain injury in an ASIC1a-dependent manner.CONCLUSIONS:Our study identifies Triol as a novel ASIC inhibitor, which may serve as a new pharmacological tool for studying ASICs and may also be developed as a potential drug for treating stroke.

06 Oct 2023·Science Advances

Enhanced harm detection following maternal separation: Transgenerational transmission and reversibility by inhaled amiloride

Article

Author: Rossignol, Orlane ; De Koninck, Yves ; Deguire, Jasmin ; D'Amato, Francesca R ; Battaglia, Marco ; Godin, Antoine G ; Lorenzo, Louis-Etienne

Early-life adversities are associated with altered defensive responses. Here, we demonstrate that the repeated cross-fostering (RCF) paradigm of early maternal separation is associated with enhancements of distinct homeostatic reactions: hyperventilation in response to hypercapnia and nociceptive sensitivity, among the first generation of RCF-exposed animals, as well as among two successive generations of their normally reared offspring, through matrilineal transmission. Parallel enhancements of acid-sensing ion channel 1 (ASIC1), ASIC2, and ASIC3 messenger RNA transcripts were detected transgenerationally in central neurons, in the medulla oblongata, and in periaqueductal gray matter of RCF-lineage animals. A single, nebulized dose of the ASIC-antagonist amiloride renormalized respiratory and nociceptive responsiveness across the entire RCF lineage. These findings reveal how, following an early-life adversity, a biological memory reducible to a molecular sensor unfolds, shaping adaptation mechanisms over three generations. Our findings are entwined with multiple correlates of human anxiety and pain conditions and suggest nebulized amiloride as a therapeutic avenue.

03 Jul 2023·Molecular pharmaceutics

Automated Patch Clamp Screening of Amiloride and 5-N,N-Hexamethyleneamiloride Analogs Identifies 6-Iodoamiloride as a Potent Acid-Sensing Ion Channel Inhibitor.

Article

Author: Bujaroski, Richard S ; Kelso, Michael J ; Majed, Hiwa ; Ranson, Marie ; Buckley, Benjamin J ; Aboelela, Ashraf ; Rangel, Alejandra ; Adams, David J ; Finol-Urdaneta, Rocio K ; McArthur, Jeffrey R

Acid-sensing ion channels (ASICs) are transmembrane sensors of extracellular acidosis and potential drug targets in several disease indications, including neuropathic pain and cancer metastasis. The K⁺-sparing diuretic amiloride is a moderate nonspecific inhibitor of ASICs and has been widely used as a probe for elucidating ASIC function. In this work, we screened a library of 6-substituted and 5,6-disubstituted amiloride analogs using a custom-developed automated patch clamp protocol and identified 6-iodoamiloride as a potent ASIC1 inhibitor. Follow-up IC₅₀ determinations in tsA-201 cells confirmed higher ASIC1 inhibitory potency for 6-iodoamiloride 94 (hASIC1 94 IC₅₀ = 88 nM, cf. amiloride 11 IC₅₀ = 1.7 μM). A similar improvement in activity was observed in ASIC3-mediated currents from rat dorsal root ganglion neurons (rDRG single-concentration 94 IC₅₀ = 230 nM, cf. 11 IC₅₀ = 2.7 μM). 6-Iodoamiloride represents the amiloride analog of choice for studying the effects of ASIC inhibition on cell physiology.

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