RTI-13951-33 hydrochloride is a potent, selective, and brain-penetrant GPR88 agonist, exhibiting an EC50 of 25 nM in vitro cAMP functional assay. It significantly reduces alcohol reinforcement and intake behaviors in rats [1].

GPR88:（EC50）25 nM

RTI-13951-33 is a potent and selective GPR88 agonist that effectively crosses the blood-brain barrier, demonstrating a significant effect with an EC50 value of 25 nM in GPR88 cAMP functional assays. It also increases [35S]-GTPγS binding in the mouse striatum with an EC50 of 535 nM, a response absent in GPR88 knockout (KO) mice. Despite its primary activity, RTI-13951-33 exhibits weak affinities for the kappa opioid receptor (KOR; Ki, 2.29 μM), the vesicular monoamine transporter (VMAT; Ki, 4.23 μM), and a moderate affinity for the serotonin transporter (SERT; Ki, 0.75 μM). However, it demonstrates poor inhibition of SERT, with an IC50 of 25.1±2.7 μM.

RTI-13951-33 (10 and 20 mg/kg, i.p.) reduces alcohol lever responses in a rat model of alcohol self-administration dose-dependently, demonstrating sufficient brain penetration with a half-life of 48 minutes in plasma and 87 minutes in brain [1].