Tandem sulfur-containing amino acids are epicritical determinants of dopamine D-2 receptor pharmacology

The conserved aspartic acid that is required for ligand binding to the dopa mine D-2 receptor is followed by three tandem sulfur-containing amino acids . While previous point mutation studies did not reveal any single one of th ese residues as being critical for ligand binding, we now show that simulta neously substituting all three with isovolumetric, non sulfur-containing am ino acids results in large decreases in the binding affinity for dopamine, (-)-raclopride and 7-(-4(4-(2,3-dichlorophenyl)-1-piperazinyl)butyloxy)-3,4 -dihydro-2(1H)-quinolinone (aripiprazole), but not for methylspiperone or a llosteric modulators. (C) 2000 Elsevier Science B.V. All rights reserved.