1401460-92-1Relevant academic research and scientific papers
Niclosamide is a Negative Allosteric Modulator of Group I Metabotropic Glutamate Receptors: Implications for Neuropathic Pain
Ai, Ni,Wood, Richard D.,Yang, Eric,Welsh, William J.
, p. 3044 - 3056 (2016)
Purpose: Novel therapeutics are greatly needed that target specific pathological receptors and pathways involved in Neuropathic Pain (NP). Extending our previous work published in this Journal on Group I metabotropic glutamate receptor (mGluR) modulators, we now investigate the therapeutic potential of niclosamide in modulating aberrant glutamate transmission in NP. Method: Calcium mobilization assays and cross-receptor selectivity experiments are conducted to characterize the pharmacological activity of niclosamide. A focused series of niclosamide analogues is then prepared to elucidate key structural determinants that emerged from computational molecular modeling analysis on drug-receptor interactions. Finally, niclosamide and a carbamate derivative are studied to assess their efficacy in an NP-evoked mechanical hyperalgesia model in rats. Results: Niclosamide is a low-nanomolar allosteric antagonist of Group I mGluRs with high selectivity for Group I over homologous Group III mGluRs. The phenolic hydroxyl group of niclosamide forms a crucial hydrogen bond with mGluR1/5. Its bioactive coplanar conformation is further stabilized by the nitro substituent on the B ring and an intramolecular bond. Mechanical hyperalgesia in NP rats is reversed by niclosamide through three different dosing routes. Conclusion: To our knowledge, this is the first report of the salicylanilide class of compounds as potential treatments for NP.
Salicylanilide inhibitors of Toxoplasma gondii
Fomovska, Alina,Mui, Ernest,McLeod, Rima,Wood, Richard D.,Welsh, William J.,Dubey, Jitenter P.,Ferreira, Leandra R.,Hickman, Mark R.,Lee, Patricia J.,Leed, Susan E.,Auschwitz, Jennifer M.,Sommerville, Caroline,Woods, Stuart,Roberts, Craig
, p. 8375 - 8391,17 (2020/09/15)
Toxoplasma gondii (T. gondii) is an apicomplexan parasite that can cause eye disease, brain disease, and death, especially in congenitally infected and immune-compromised people. Novel medicines effective against both active and latent forms of the parasite are greatly needed. The current study focused on the discovery of such medicines by exploring a family of potential inhibitors whose antiapicomplexan activity has not been previously reported. Initial screening efforts revealed that niclosamide, a drug approved for anthelmintic use, possessed promising activity in vitro against T. gondii. This observation inspired the evaluation of the activity of a series of salicylanilides and derivatives. Several inhibitors with activities in the nanomolar range with no appreciable in vitro toxicity to human cells were identified. An initial structure-activity relationship was explored. Four compounds were selected for evaluation in an in vivo model of infection, and two derivatives with potentially enhanced pharmacological parameters demonstrated the best activity profiles.
