Design and synthesis of [(2,3-dichlorophenyl)piperazin-1-yl]alkylfluorenylcarboxamides as novel ligands selective for the dopamine D3 receptor subtype

The dopamine D-3 receptor subtype has been recently targeted as a potential neurochemical modulator of the behavioral actions of psychomotor stimulants, such as cocaine. However, definitive behavioral investigations have been hampered by the lack of highly selective D-3 agonists and antagonists. In an attempt to design a novel class of D-3 ligands with which to study this receptor system, a series of chemically divergent compounds that possessed various structural features that exist within several classes of reputed D-3 agents was screened and compared to the recently reported NGB 2904 (58b). On the basis of these results, a novel series of compounds was designed that included functional moieties that were required for high-affinity and selective binding to D-3 receptors. All the compounds in this series included an aryl-substituted piperazine ring, a varying alkyl chain linker (C3-C5), and a terminal aryl amide. The compounds were synthesized and evaluated in vitro for binding in CHO cells transfected with human D-2, D-3, or D-4 receptor cDNAs. D-3 binding affinities ranged from K-i = 1.4 to 1460 nM. The most potent analogue in this series, 51, demonstrated a D-3/D-2 selectivity of 64 and a D-3/D-4 selectivity of 1300. Structure-activity relationships for this class of ligands at D-3 receptors will provide new leads toward the development of highly selective and potent molecular probes that will prove useful in the elucidation of the role D-3 receptors play in the psychomotor stimulant and reinforcing properties of cocaine.