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The insecticides carbaryl and carbofuran show high affinity for hMT 2 melatonin receptors (662.12)
Author(s) -
PopovskaGorevski Marina,
Dubocovich Margarita,
Rajnarayanan Rajendram
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.662.12
Subject(s) - carbofuran , carbaryl , receptor , chemistry , agonist , melatonin receptor , melatonin , gtp' , biochemistry , biology , endocrinology , enzyme , pesticide , agronomy
Carbaryl (1‐naphthyl methylcarbamate) and carbofuran (2,3‐dihydro‐2,2‐dimethyl‐7‐benzofuranyl methylcarbamate) are among the most toxic insecticides, known to increase diabetes risk. Using an integrated pharmacoinformatics‐molecular docking approach, we found carbaryl and carbofuran to be structurally similar to melatonin. These compounds docked into our predictive 3D model of the MT 2 melatonin receptor with relatively high binding affinity scores. Carbaryl and carbofuran then were tested for competition with 2‐[ 125 I]‐iodomelatonin (300nM) binding to hMT 1 or hMT 2 receptors stably expressed in CHO cells. Biphasic competition curves suggest that carbaryl binds to two affinity states of the hMT 1 (IC 50 Hi=6.8nM, IC 50 Lo=22µM) and hMT 2 (IC 50 Hi=16nM, IC 50 Lo= 0.9μM) receptors while carbofuran binds two sites on the hMT 2 (IC 50 Hi=27nM, IC 50 Lo=11μM) receptor. Compared to carbaryl, carbofuran affinity for hMT 2 was lower, but it showed selectivity, as it did not compete for hMT 1 binding. GTP (100 mM) did not affect binding affinity of carbaryl for either hMT 1 or hMT 2 receptors. However, GTP significantly decreased the affinity of carbofuran for hMT 2 receptors suggesting potential agonist efficacy. These data support the utility of molecular modeling for screening potential melatonin ligands and suggest that carbaryl and carbofuran could interact with pancreatic MT 2 receptors, known to affect glucose homeostasis and insulin secretion. Grant Funding Source : Supported by UB Funds