N-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl, butenyl and butynyl}arylcarboxamides as novel dopamine D₃ receptor antagonists

The dopamine D₃ receptor subtype has been targeted as a potential neurochemical modulator of the behavioral actions of psychomotor stimulants, such as cocaine. Previous synthetic studies provided structural requirements for high affinity binding to D₃ receptors which included a 2,3-dichloro-phenylpiperazine linked to an arylamido function via a butyl chain. To reduce lipophilicity of these agents and further investigate optimal conformation, a second series of 15 novel ligands was designed that included heteroaromatic substitution and unsaturated alkyl linkers. These compounds were synthesized and evaluated for binding at rat D₃ and D₂ receptors stably expressed in Sf9 cells. D₃ binding affinities ranged from K_i=0.6-1080 nM, with a broad range of D₃/D₂ selectivities (2-97). The discovery of potent, selective and bioavailable D₃ receptor ligands will provide essential molecular probes to elucidate the role D₃ receptors play in the psychomotor stimulant and reinforcing effects of cocaine.