Biological Insights of the Dopaminergic Stabilizer ACR16 at the Binding Pocket of Dopamine D2 Receptor.

The dopamine D2 receptor (D2R) plays an important part in the human central nervous system and it is considered to be a focal target of antipsychotic agents. It is structurally modeled in active and inactive states, in which homodimerization reaction of the D2R monomers is also applied. The ASP2314 (also known as ACR16) ligand, a D2R stabilizer, is used in tests to evaluate how dimerization and conformational changes may alter the ligand binding space and to provide information on alterations in inhibitory mechanisms upon activation. The administration of the D2R agonist ligand ACR16 [3 H](+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol ((+)PHNO) revealed Ki values of 32 nM for the D2high R and 52 μM for the D2low R. The calculated binding affinities of ACR16 with post processing molecular dynamics (MD) simulations analyses using MM/PBSA for the monomeric and homodimeric forms of the D2high R were -9.46 and -8.39 kcal/mol, respectively. The data suggests that the dimerization of the D2R leads negative cooperativity for ACR16 binding. The dimerization reaction of the D2high R is energetically favorable by -22.95 kcal/mol. The dimerization reaction structurally and thermodynamically stabilizes the D2high R conformation, which may be due to the intermolecular forces formed between the TM4 of each monomer, and the result strongly demonstrates dimerization essential for activation of the D2R.