N ‐(4‐(4‐(2‐Halogenophenyl)piperazin‐1‐yl)butyl) Substituted Cinnamoyl Amide Derivatives as Dopamine D 2 and D 3 Receptor Ligands

A series of eight substituted N ‐(4‐(4‐(2‐halogenophenyl)piperazin‐1‐yl)butyl)‐3‐phenylacryl amide derivatives have been synthesized and screened for binding affinities at dopamine hD 2 and hD 3 receptors. All compounds have shown high to remarkable receptor affinities and some have led to distinct selectivity for D 3 receptors. Highest D 3 ‐receptor affinity has been observed for 3‐(4‐aminophenyl)‐ N ‐(4‐(4‐(2‐fluorophenyl)piperazin‐1‐yl)butyl)acryl amide (hD 3 K i 0.9 nM; hD 2 K i 17.4 nM). Selectivity ratio has been best for 3‐(4‐chlorophenyl)‐ N ‐(4‐(4‐(2‐fluorophenyl)piperazin‐1‐yl)butyl)acryl amide with a 56‐fold preference for hD 3 versus hD 2 . A functional activity test has been performed by a mitogenesis test for N ‐(4‐(4‐(2‐fluorophenyl)piperazin‐1‐yl)butyl)‐3,3‐diphenylacryl amide, which, surprisingly, has shown full agonist properties.