Background And Purpose: Purinoceptors containing the P2X3 subunit (P2X3 homotrimeric and P2X2/3 heterotrimeric) are members of the P2X family of ion channels gated by ATP and may participate in primary afferent sensitization in a variety of pain-related diseases. The current work describes the in vitro pharmacological characteristics of AF-353, a novel, orally bioavailable, highly potent and selective P2X3/P2X2/3 receptor antagonist.
Experimental Approach: The antagonistic potencies (pIC(50)) of AF-353 for rat and human P2X3 and human P2X2/3 receptors were determined using methods of radioligand binding, intracellular calcium flux and whole cell voltage-clamp electrophysiology.
Key Results: The pIC(50) estimates for these receptors ranged from 7.3 to 8.5, while concentrations 300-fold higher had little or no effect on other P2X channels or on an assortment of receptors, enzymes and transporter proteins. In contrast to A-317491 and TNP-ATP, competition binding and intracellular calcium flux experiments suggested that AF-353 inhibits activation by ATP in a non-competitive fashion. Favourable pharmacokinetic parameters were observed in rat, with good oral bioavailability (%F = 32.9), reasonable half-life (t(1/2) = 1.63 h) and plasma-free fraction (98.2% protein bound).
Conclusions And Implications: The combination of a favourable pharmacokinetic profile with the antagonist potency and selectivity for P2X3 and P2X2/3 receptors suggests that AF-353 is an excellent in vivo tool compound for study of these channels in animal models and demonstrates the feasibility of identifying and optimizing molecules into potential clinical candidates, and, ultimately, into a novel class of therapeutics for the treatment of pain-related disorders.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2938810 | PMC |
http://dx.doi.org/10.1111/j.1476-5381.2010.00796.x | DOI Listing |
J Med Chem
March 2024
Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
The high lethality of infections and the emergence of antibiotic resistance make the development of new antibiotics urgent. Our previous work identified a hit compound () as a novel () dihydrofolate reductase (DHFR) inhibitor. Herein, we analyzed the antimicrobial profile of and performed a comprehensive structure-activity relationship (SAR) assay based on .
View Article and Find Full Text PDFChem Biol Drug Des
December 2022
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
mtbDHFR-targeting inhibition has become a promising approach for tuberculosis treatment. In the current research, a multi-step virtual screening effort toward ZINC and MCE databases was devoted to discover novel mtbDHFR inhibitors. Based on binding affinity of small molecules through molecular docking study in AutoDock Vina, the number of compounds was reduced to 952,688.
View Article and Find Full Text PDFInt Neurourol J
December 2017
Regenerative Medicine and Tissue Engineering Program-Urology, Houston Methodist Research Institute, Houston, TX, USA.
Purpose: To simultaneously monitor electrical discharges in various bladder regions and the external urethral sphincter (EUS) during voiding contractions, and to assess the functional role of myogenic modulation of the lower urinary tract (LUT) by ionotropic purinergic receptors containing the P2X3 subunit.
Methods: Female Sprague-Dawley rats were anesthetized with urethane, and implanted with a suprapubic catheter for open cystometry. Flexible microelectrodes were placed ventrally in the bladder dome, upper bladder, lower bladder, and bladder base, along with the middle section of the exposed EUS.
Br J Pharmacol
July 2010
Department of Inflammation Discovery, Roche Palo Alto, Palo Alto, CA, USA.
Background And Purpose: Purinoceptors containing the P2X3 subunit (P2X3 homotrimeric and P2X2/3 heterotrimeric) are members of the P2X family of ion channels gated by ATP and may participate in primary afferent sensitization in a variety of pain-related diseases. The current work describes the in vitro pharmacological characteristics of AF-353, a novel, orally bioavailable, highly potent and selective P2X3/P2X2/3 receptor antagonist.
Experimental Approach: The antagonistic potencies (pIC(50)) of AF-353 for rat and human P2X3 and human P2X2/3 receptors were determined using methods of radioligand binding, intracellular calcium flux and whole cell voltage-clamp electrophysiology.
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!