Novel bivalent ligands for D2/D3 dopamine receptors: Significant co-operative gain in D2 affinity and potency

This report describes development of a series of novel bivalent molecules with a pharmacophore derived from the D2/D3 agonist 5-OH-DPAT. Spacer length in the bivalent compounds had a pronounced influence on affinity for D2 receptors. A 23-fold increase of D2 affinity was observed at a spacer length of 9 or 10 (compounds 11d and 14b) compared to monovalent 5-OH-DPAT (Ki; 2.5 and 2.0 vs. 59 nM for 11d and 14b vs. 5-OH-DPAT, respectively). Functional potency of 11d and 14b indicated a 24- and 94-fold increase in potency at the D2 receptor compared to 5-OH-DPAT (EC50; 1.7 and 0.44 vs. 41 nM for 11d and 14b vs. 5-OH-DPAT, respectively). These are the most potent bivalent agonists for D2 receptor known to date. This synergism is consonant with cooperative interaction at the two orthosteric binding sites in the homodimeric receptor.