Dopamine D(3) receptor partial agonism has been suggested as a potential therapeutic intervention in cocaine addiction. RGH-237 [N-{4-[4-(3-aminocarbonyl-phenyl)-piperazin-1-yl]-butyl}-4-bromo-benzamide] was identified as a novel selective dopamine D(3) receptor partial agonist and used for testing this hypothesis in animal models. The compound showed nanomolar affinity to human (K(i) = 6.7 nM) and rat (K(i) = 1.6 nM) D(3) receptors with an intrinsic activity of approximately 50%. It possessed several hundredfold selectivity over the D(2) receptor. The molecule bound with moderate (100-250 nM) affinity to 5-hydroxytryptamine 1A (5-HT(1A)) and nonselectively labeled opiate receptors. RGH-237 proved to be practically inactive on more than 40 other targets, including monoaminergic, cholinergic, GABAergic, and glutamatergic receptors. In rats orally administered RGH-237 was well and rapidly absorbed yielding 41% oral bioavailability. At its pharmacologically active dose (10 mg/kg p.o.), the brain concentration of RGH-237 reached 110 ng/g. Its blood and brain levels were sustained for 3 h. RGH-237 at the oral dose of 10 mg/kg moderately but significantly inhibited the acquisition of cocaine-induced place preference, although by itself, it had no place-conditioning effect. The compound did not affect fixed ratio 1 cocaine self-administration. In a reinstatement paradigm of cocaine self-administration, the compound potently and dose-dependently blocked the cue-induced cocaine-seeking behavior of rats at 10 and 30 mg/kg oral doses. RGH-237 did not affect seeking activity for natural rewards, such as sucrose and water. It did not exert notable effect on spontaneous motor activity of rats. Our results demonstrate that selective D(3) partial agonists may be an effective therapeutic means in the treatment of cocaine abuse.