SK609, a novel dopamine D3 receptor agonist and norepinephrine transporter blocker with putative pro-cognitive actions, does not induce psychostimulant-like increases in risky choice during probabilistic discounting.

Rationale: Psychostimulants, such as amphetamine (AMPH) and methylphenidate (MPH), non-selectively elevate extracellular concentrations of the catecholamine neurotransmitters, dopamine (DA) and norepinephrine (NE), and are common pharmacological strategies used to improve prefrontal cortex (PFC)-dependent cognitive dysfunction. However, this approach can be problematic given AMPH has been shown to increase preference for risky choices in a rodent assay of risk/reward decision making. SK609 is a novel NE reuptake blocker that selectively activates DA D3 receptors without affinity for the DA transporter.

Dopamine D Receptor-Selective Compounds Reveal Structure-Activity Relationships that Engender Agonist Efficacy.

The dopamine D receptor (DR) plays important roles in cognition, attention, and decision making. Novel DR-selective ligands have promise in medication development for neuropsychiatric conditions, including Alzheimer's disease and substance use disorders. To identify new DR-selective ligands, and to understand the molecular determinants of agonist efficacy at DR, we report a series of eighteen novel ligands based on the classical DR agonist A-412997 (1, 2-(4-(pyridin-2-yl)piperidin-1-yl)- N-( m-tolyl)acetamide).