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 Ki=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.