Dopamine has been implicated as the primary neurotransmitter associated with the psychomotor stimulant and reinforcing effects of cocaine. These findings have resulted in intensive efforts to characterize and elucidate the roles of the various dopamine receptor subtypes in the pharmacology and abuse liability of this drug of abuse. In this pursuit, the dopamine D3 receptor subtype has been recently targeted. However, definitive behavioral investigations have been hampered by the lack of highly selective D3 agonists and antagonists. Novel series of compounds were designed, based on NGB 2904, that included functional moieties that were previously determined by our laboratory and others for high affinity and selective D3 receptor binding. All the compounds included a 2,3-dichloro-substituted phenylpiperazine, a four carbon linking chain with varying saturation (butyl, trans butenyl, cis-butenyl and butynyl) and a terminal aryl amide. These novel compounds were synthesized, purified, chemically characterized and evaluated in vitro for binding in HEK 293cells transfected with human D2, D3, or D4 receptor cDNAs. D3 receptor binding affinities ranged from Ki=0.5-500 nM. The most potent analogs in this series, demonstrated D3/D2 selectivity of >130 and a D3/D4 selectivity of >1000. Functional evaluation in vitro using a mitogenesis assay in D3 or D2 receptor transfected CHO cells demonstrated that these compounds were either potent antagonists or partial agonists at D3 receptors and were selective over D2 receptors in this function. Structure-activity relationships demonstrated that trans-butenyl linker provided additional D3 selectivity as compared to the other linking chains. Further, replacement of the sterically bulky aryl ring system with various heteroaryl groups served to retain high affinity and selectivity for D3, while decreasing lipophilicity, as compared to the parent compound NGB 2904. The latter goal of reducing lipophilicity of the most potent agents was to improve physico-chemical properties that would provide a more favorable pharmacokinetic/bioavailability profile than the currently existing D3 agents. Although some of the compounds displayed moderate to high affinity for D2 receptors, none of the compounds displayed appreciable affinity for D4. The most potent and selective compounds, of this series, were synthesized in multigram quantities and are currently being evaluated in several animal models of cocaine and methamphetamine abuse, in both rodents and primates. Although clinical efficacy of these agents has yet to be substantiated, the development of highly selective and potent molecular probes will prove useful in the elucidation of the role D3 receptors play in the psychomotor stimulant and reinforcing properties of cocaine and methamphetamine.
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