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Super sume pro license check validated7/20/2023 In silico models can be used to prioritize chemicals for toxicological evaluation to reduce the amount of costly pharmacological testing and enable early alerts for newly designed compounds. Many EDCs elicit their toxicological effects through nuclear hormone receptors, like the estrogen receptor α (ERα). Consistent with the experimental data, this model illustrates the interactions between a variety of subtype-selective ligands and the wild-type D2, mutant D2, or wild-type D4 receptors.Įndocrine disrupting chemicals (EDCs) pose a significant threat to human health, society and the environment. Utilizing a new docking technique that incorporates receptor backbone flexibility, the three non-conserved amino acids that encompass the TM2/3 microdomain were found to account in large part for the differences in intermolecular steric contacts between the ligands and receptors. Our study demonstrates for the first time that the TM2/3 microdomain of the D2 dopamine receptor not only regulates the selective affinity of ligands, but in selected cases can also regulate their function. In contrast to RBI-257 which is an antagonist at all receptors, L-750,667 is a partial agonist at the wild-type D2 but an antagonist at both the mutant D2 and wild-type D4 receptors. Consistent with their higher affinity for the mutant than for the wild-type receptor, concentrations of L-750,667 or RBI-257 that produced large reductions in the potency of quinpirole’s functional response in the mutant did not significantly reduce quinpirole’s functional response in the wild-type D2 receptor. The two ligands with the greatest improvement in affinity for the D2 mutant receptor pyridine (L-750,667) and 1-4-aminopiperidine (RBI-257)] were investigated in functional assays. Five of the selective ligands were observed to have 21-fold to 293-fold increases in D2 receptor affinity when three non-conserved amino acids in TM2 and TM3 were mutated to the corresponding D4 amino acids. To better understand the specific interactions of subtype-selective ligands with dopamine receptor subtypes, seven ligands with high selectivity (>120-fold) for the D4 subtype of dopamine receptor were tested on wild-type and mutant D2 receptors. ![]() The D2 dopamine receptor is an important therapeutic target for the treatment of psychotic, agitated, and abnormal behavioral states.
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