Effects of RTI-567 on the Neuropeptide S System.

Anxiety and post-traumatic stress have increasingly become more prominent disorders and options for treatment remain limited. One of the most prescribed therapeutics are benzodiazepines. Unfortunately, these anxiolytics have negative side effects and are not as effective in the long term. The recently discovered Neuropeptide S (NPS) system may lead to an alternative, potentially improved, line of therapeutics. This system consists of a known endogenous neuropeptide, Neuropeptide S and a G-protein-coupled receptor termed the Neuropeptide S receptor (NPSR). Activation of this receptor leads to an increase in intracellular calcium and a mobilization of cAMP. This is associated with behavioral phenotypes such as anxiolysis, enhanced memory consolidation, and hyperlocomotion. The NPSR is highly expressed in the amygdala linking the NPS system with fear and anxiety. Previously, as part of our ongoing drug discovery program, a biased agonist (RTI-263) was identified that preferentially enhances the calcium signaling pathway over the cAMP pathway following NPSR binding. This biased agonist also reduced hyperlocomotion or arousal observed with NPS, while maintaining the anxiolytic component. In the present study we test another compound (RTI-567) using classic anxiolytic, locomotor, and memory testing paradigms such as the light dark box, open field, and inhibitory avoidance. Our overall goal is to identify novel synthetic agonists with reduced side effects and improved long-term efficacy.