Repurposing antipsychotic and sleep disorder drugs as anti-parasitics
Antipsychotic and sleep disorder drugs represent a rapidly growing, global market (1). Novel drugs targeting melatonin (2), serotonin (3), dopamine (4), and GABA (5) receptors are being developed. Historically, related compounds have been identified as demonstrating activity against flatworms and the model nematode Caenorhabditis elegans, but nothing has been done to reconcile the recent growing diversity of chemical derivatives with potential activity against parasitic worms (6).
Melatonin is a well-known regulator of circadian rhythms in mammals, and Prazosin, an agonist of the mammalian melatonin 3 receptor, triggers various defects in C. elegans (7). Melatonin has also been shown to promote protective effects in mice infected with Schistosoma mansoni (8).
Ivermectin is a potent anti-parasitic which agonizes GABA receptors, causing flaccid paralysis and parasite death. Benzodiazepine and non-benzodiazepine GABA receptor agonists could therefore prove effective anthelmintics. Ivermectin exposure has also been found to enhance binding of certain benzodiazepine-derivatives in rats (9) providing some rationale for exploring combinatorial therapies. Benzodiazepine derivatives have historically proven effective as anti-schistosomals (10), providing further evidence of anti-parasitic efficacy within the family.
Serotonin impacts motility and carbohydrate metabolism in flatworms (11), and nematodes (12). Dopamine impacts various behaviours in nematodes (13), and reduces motility in flatworms (14).
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What is novel in it. Similar studies have been done in detail. I am giving you one reference of Sarah kinnings where repositioning of drugs was studies to find drug for tuberculosis. They used entacopone used for alzheimers in docking studies of enoyl reductase present in M.tb. Repositioning of drugs is feasible and happens because proteins share folds. Sometimes different drug targets also share folds that leads to having similar active sites in the drug targets and thus are useful in repositioning of drugs.
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hemendra yadav · 7 Feb, 2016
The above described studies which i have discussed were conducted in 2009 and new algorithms have developed like SOSA, SOIPPA etc for conducting such studies.
hemendra yadav · 9 Feb, 2016
Hello Hemendra, I see that your comment was made quite a while ago, but on seeing it, I will reply nonetheless. You are correct that drugs are repurposed / repositioned often. My suggestion above relates specifically to a particular class of drugs, which have not previously been assessed as anti-parasitic drugs in any large scale trial. If you could point me to a relevant study undertaking this work I will of course delete the initial suggestion. Best wishes, Johnathan.
Johnathan Dalzell · 18 Jul, 2017
Wouldn't a good anti-parasite have the property to have negligible effect on human beings and other organisms we do NOT want to be affected? Do you think this is the case for bezodiazepines and the like? Just asking for your consideration
Enea Parimbelli · 17 Feb, 2021