Discovery of 4-arylthiophene-3-carboxylic acid as inhibitor of ANO1 and its effect as analgesic agent

Abstract

Anoctamin 1 (ANO1) is a kind of calcium-activated chloride channel involved in nerve depolarization. ANO1 inhibitors display significant analgesic activity by the local peripheral and intrathecal administration. In this study, several thiophenecarboxylic acid and benzoic acid derivatives were identified as novel ANO1 inhibitors through the shape-based virtual screening, among which the 4-arylthiophene-3-carboxylic acid analogues with the best ANO1 inhibitory activity were designed, synthesized and compound 42 (IC 50 = 0.79 μmol/L) was finally obtained. Compound 42 selectively inhibited ANO1 without affecting ANO2 and intracellular Ca 2+ concentration. Subsequently, the analgesic effect was investigated by intragastric administration in pain models. Compound 42 significantly attenuated allodynia which was induced by formalin and chronic constriction injury. Through homology modeling and molecular dynamics, the binding site was predicted to be located near the calcium-binding region between α 6 and α 8. Our study validates ANO1 inhibitors having a significant analgesic effect by intragastric administration and also provides selective molecular tools for ANO1-related research.

Identification of a druggable pocket of the calcium-activated chloride channel TMEM16A in its open state

“…High-throughput drug screening and computer-aided drug design have identified an array of TMEM16A activators and potentiators, among which ETX001, a potentiator of TMEM16A, has entered clinical trials as therapeutic agent for cystic fibrosis ( 7 ). Meanwhile, a large number of TMEM16A inhibitors have been identified, including natural products Cepharanthine ( 8 ), Evodiamine ( 9 ), Honokiol ( 10 ), and Luteolin ( 11 ) and synthetic compounds Ani9 ( 12 ), CaCC inh -A01 ( 13 ), T16A inh -A01 ( 14 ), Monna ( 15 ), and 4-arylthiophene-3-carboxylic acid ( 16 ). These inhibitors have shown potential therapeutic effects in the laboratory against TMEM16A-related diseases such as hypertension, cancer, and secretory diarrhea ( 7 ).…”

Single-cell RNA sequencing uncovers a neuron-like macrophage subset associated with cancer pain

“…S12). More interestingly, we detected a specific expression of pain receptors Ano1 ( 48 ) and Trpc1 ( 49 ) in the MNTs ( Fig. 4H ) and connection of synaptophysin-expressing MNTs in the LLC tumor in vivo and neurocircuit formation of BMDM-derived MNTs in vitro (fig.…”

Deciphering the Mechanism of Gilteritinib Overcoming Lorlatinib Resistance to the Double Mutant I1171N/F1174I in Anaplastic Lymphoma Kinase

“…The four systems were performed with two rounds of energy minimization as reported previously by a combination of steepest descent and conjugate gradient minimizations ( Lu et al, 2019b ; Mahalapbutr et al, 2020 ; Shi et al, 2020 ; Vatansever et al, 2020 ; Wang et al, 2021a ; Lu et al, 2021b ). Afterwards, 500 ps heating, and 1,000 ps equilibration at 300 K under the NVT ensemble were performed with all heavy atoms of protein-ligand complexes fixed by a 10 kcal/(mol Å 2 ) force constant.…”