title: Carbamate Insecticides Target Human Melatonin Receptors.
abstract: Carbaryl (1-naphthyl methylcarbamate) and carbofuran (2,3-dihydro-2,2-dimethyl-7-benzofuranyl methylcarbamate) are among the most toxic insecticides, implicated in a variety of diseases including diabetes and cancer among others. Using an integrated pharmacoinformatics based screening approach, we have identified these insecticides to be structural mimics of the neurohormone melatonin and were able to bind to the putative melatonin binding sites in MT1and MT2melatonin receptors in silico. Carbaryl and carbofuran then were tested for competition with 2-[125I]-iodomelatonin (300 pM) binding to hMT1or hMT2receptors stably expressed in CHO cells. Carbaryl and carbofuran showed higher affinity for competition with 2-[125I]-iodomelatonin binding to the hMT2compared to the hMT1melatonin receptor (33 and 35-fold difference, respectively) as predicted by the molecular modeling. In the presence of GTP (100 μM), which decouples the G-protein linked receptors to modulate signaling, the apparent efficacy of carbaryl and carbofuran for 2-[125I]-iodomelatonin binding for the hMT1melatonin receptor was not affected but significantly decreased for the hMT2melatonin receptor compatible with receptor antagonist/inverse agonist and agonist efficacy, respectively. Altogether, our data points to a potentially new mechanism through which carbamate insecticides carbaryl and carbofuran could impact human health by altering the homeostatic balance of key regulatory processes by directly binding to melatonin receptors.
authors.affiliation: Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo , Buffalo, New York 14221, United States.
authors.forename: Marina
authors.initials: M
authors.lastname: Popovska-Gorevski
authors.affiliation: Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo , Buffalo, New York 14221, United States.
authors.forename: Margarita L
authors.initials: ML
authors.lastname: Dubocovich
authors.affiliation: Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo , Buffalo, New York 14221, United States.
authors.forename: Rajendram V
authors.identifier: 0000-0003-0843-7787
authors.initials: RV
authors.lastname: Rajnarayanan
mesh_terms: D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D002219:Carbamates / Q000378:metabolism / Q000633:toxicity*; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D007306:Insecticides / Q000378:metabolism / Q000633:toxicity*; D008024:Ligands; D062105:Molecular Docking Simulation; D044094:Receptors, Melatonin / Q000187:drug effects* / Q000378:metabolism
chemical_list: D002219:Carbamates; D007306:Insecticides; D008024:Ligands; D044094:Receptors, Melatonin