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. In an attempt to design a novel class of D3 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 D3 agents was screened and compared to the recently reported D3 antagonist, NGB 2904. Based on these results, a novel series of compounds was designed that included functional moieties that were required for high affinity and selective D3 receptor binding. All the compounds in this series included an aryl-substituted piperazine ring, varying alkyl chain linker (C3-C5) and a terminal aryl amide. These novel compounds were synthesized, purified, chemically characterized and evaluated in vitro for binding in CHO cells transfected with human D2, D3, or D4 receptor cDNAs. D3 binding affinities ranged from Ki=1.4-1460 nM. The most potent analog in this series, demonstrated a D3/D2 selectivity of 64 and a D3/D4 selectivity of 1300. Structure-activity relationships demonstrated that the 2,3-dichloro-substituted phenylpiperazine was required for high affinity binding at D3, wherein every compound with this substituent was more potent than its unsubstituted homologue. The optimum alkyl chain length, between the amido-aryl function and the phenylpiperazine was four carbons. Although the 5-carbon linked compounds exhibited reasonably high affinity for D3, D2 affinity was also very high. The 3-carbon chained analogs resulted in less potent binding at D3, which was supported by previously obtained data with a series of rimcazole analogs, wherein the carbazole ring system was linked to the piperazine ring with a 3-carbon chain. The position of the amide-linkage on the fluorenyl ring appears to be optimal at either the 3- or 4-positions. 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 compound, of this series, has been synthesized in multigram quantities and is being evaluated in several animal models of cocaine and methamphetamine abuse. Novel ligands have now been designed and are currently being prepared with the goal of retaining high affinity for D3 receptors, but improving physico-chemical properties that will provide a more favorable pharmacokinetic/bioavailability profile than the currently existing D3 agents. 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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