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. We have prepared the known D3 antagonist NGB 2904 in multi-gram quantities for acute and chronic behavioral testing. This compound demonstrated in vivo D3 antagonist actions and attenuated cocaine self-administration under a progressive ratio schedule. NGB 2904 also blocked cocaine-induced reinstatement of drug seeking behavior, an animal model of relapse. We have also designed and synthesized novel series of compounds, based on NGB 2904. All the compounds included either a 2,3-dichloro- or 2-methoxy-substituted- phenylpiperazine, a four carbon linking chain with varying saturation (butyl, hydroxybutyl, and trans butenyl) and a terminal aryl amide. Evaluation for in vitro binding in HEK 293 cells transfected with human D2, D3, or D4 receptor cDNAs resulted in D3 binding affinities ranging from Ki=0.3-500 nM. The most potent analogs in this series, demonstrated D3/D2 selectivity of >200 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 the trans-butenyl linker provided additional D3 selectivity as compared to the saturated linking chain. Moreover, addition of a hydroxy group in the 2- or 3-position of the butyl linker also gave several high selective and potent D3 antagonists or partial agonists. 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. Several of the most potent and selective compounds of this series have been synthesized in multi-gram quantities and are currently being evaluated in several animal models of cocaine and methamphetamine abuse, in both rodents and primates. Thus far, PG01037 attenuated dopamine-agonist-induced yawning in rats or monkeys in a dose dependent manner, indicating selective D3 antagonist action in vivo. Further, phMRI studies have shown that PG01037 localizes in D3 receptor rich regions of the living rat brain and functions as an antagonist by inducing positive cerebral blood volumes, in those regions. Chronic studies in these and additional rodent and monkey models of drug and alcohol abuse, impulsivity, and schizophrenia are underway with PG01037 and several other butenyl and hydroxy-butyl linked analogues. In addition, we have embarked on an SAR study of novel D2 antagonists, based on the parent ligand L741,626. Structural modification of this molecule has revealed important structural features that impart high affinity for D2 receptors, although improving D2/D3 selectivity has thus far remained elusive. Nevertheless, exceptionally high D2/D3 receptor affinities with some structural motifs have led to the design of compounds that may demonstrate D2 v. D3 separability in the future.