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NEUROPHARMACOLOGY

Ligand Selectivity of D₂ Dopamine Receptors Is Modulated by Changes in Local Dynamics Produced by Sodium Binding

Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York (S.S.E., H.W.); and Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas (D.F.C., J.A.S.)

We have uncovered a significant allosteric response of the D₂ dopamine receptor to physiologically relevant concentrations of sodium (140 mM), characterized by a sodium-enhanced binding affinity for a D₄-selective class of agonists and antagonists. This enhancement is significantly more pronounced in a D₂-V2.61(91)F mutant and cannot be mimicked by an equivalent concentration of the sodium replacement cation N-methyl-D-glucamine. This phenomenon was explored computationally at the molecular level by analyzing the effect of sodium binding on the dynamic properties of D₂ receptor model constructs. Normal mode analysis identified one mode (M₁₉), which is involved in the open/closed motions of the binding cleft as being particularly sensitive to the sodium effect. To examine the consequences for D₂ receptor ligand recognition, one of the ligands, L-745,870 [3-{[4-(4-chlorophenyl) piperazin-1-yl]-methyl}-1H-pyrrolo[2,3-b]pyridine or CPPMA, chlorophenylpiperazinyl methylazaindole], was docked into conformers along the M₁₉ trajectory. Structurally and pharmacologically well established ligand-receptor interactions, including the ionic interaction with D3.32(114) and interactions between the ligand aryl moieties and V2.61(91)F, were achieved only in "open" phase conformers. The docking of (-)-raclopride [3,5-dichloro-N-(1-ethylpyrrolidin-2-ylmethyl)-2-hydroxy-6-methoxybenzamide] suggests that the same binding cleft changes in response to sodium-binding perturbation account as well for the enhancements in binding affinity for substituted benzamides in the wild-type D₂ receptor. Our findings demonstrate how key interactions can be modulated by occupancy at an allosteric site and are consistent with a mechanism in which sodium binding enhances the affinity of selected ligands through dynamic changes that increase accessibility of substituted benzamides and 1,4-DAP ligands to the orthosteric site and accessibility of 1,4-DAPs to V2.61(91)F.

Address correspondence to: Dr. John A. Schetz, Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107. E-mail: jschetz{at}hsc.unt.edu