Drug abuse is a serious health problem in many areas of the world. There are no widely effective medications available to treat its underlying pathology or its clinical manifestations. The mesolimbic dopamine (DA) system shows relation in drug reward and relapse. This system originates from the DA neurons in the ventral tegmental area (VTA) in the midbrain and projects to the nucleus accumbens (NAc), prefrontal cortex (PFC), and amygdala in the forebrain. There are several useful pharmacological strategies to manipulate brain DA transmission: one is to modulate brain DA transporters, another is to modulate brain DA receptors. NGB 2904 is a selective, orally active, and brain-penetrated antagonist of dopamine D3 receptor (Ki =1.4 nM). It shows selectivity for D3 over D2, 5-HT2, α1, D4, D1, and D5 receptors. NGB 2904 antagonizes Quinpirole-stimulated mitogenesis. It can inhibit Cocaine’s rewarding effects and Cocaine-induced reinstatement of drug-seeking behavior.
NGB 2904 shows Kis of 217, 223, 642, >5000, >10000 and >10000 nM, respectively. Moreover, NGB 2904 antagonizes Quinpirole (100 nM)-stimulated mitogenesis, with an IC50 of 5.0 nM. In addition, NGB 2904 attenuates Cocaine’s rewarding effects as assessed by PR self-administration, BSR, and Cocaine-triggered reinstatement of Cocaine-seeking behavior in rats. NGB 2904 enhances amphetamine-stimulated locomotion in wild-type mice. NGB2904 may also act as a useful tool to study the role of D3 receptors in drug addiction. It also stimulates spontaneous locomotion in wild-type mice.
In summary, NGB 2904 is a dopamine D3 receptor antagonist. It inhibits cocaine’s rewarding effects and cocaine-induced reinstatement of drug-seeking behavior in rats. NGB 2904 merits further investigation as a potential agent for the treatment of cocaine addiction.