A three dimensional receptor model of the dopamine D2 receptor from computer graphic analyses of D2 agonists

Four potent D2 agonists were employed to define a primary pharmacophore for the D2 receptor. Hypothetical receptor points, representing interaction points on a receptor were built on to each molecule. These points and the nitrogen atom were averaged to give the coordinates (A) of the primary pharmacophore: R1 (0.00, 3.50, 0.00), R2 (0.00, -3.50, 0.00), R3 (5.79, 2.06, 0.00), and nitrogen (5.13, -0.63, 0.37). Eight structural classes of D2 agonists were then superimposed on to the primary pharmacophore to aid in the location of secondary binding sites. The secondary sites include two lipophilic clefts, an area of steric bulk, a region to hydrogen bond 'meta' hydroxy groups and a 'critical region' accepting methoxy and halogen substituents but not hydroxy substituents. The model has the potential to design and predict activity of novel D2 agonist compounds.