This application responds to PA-18-058 to address the epidemic levels of prescription opioid abuse and addiction
that have resulted in an appalling number of overdose deaths. Unequivocally, there is an urgent need for effective
pharmacologic treatment options for opioid use disorder (OUD) that are safe, non-addictive, and without
substantial diversion liability to address the national public health emergency. Compelling evidence suggests
that serotonin (5HT) 2A and 2C G protein-coupled receptor (GPCR) subtypes may provide a fruitful strategy to
achieve this goal. In this regard, 5HT2C agonists can reduce self-administration and block relapse-related drug-
seeking behavior in rodents and monkeys. This has prompted development of 5HT2C-specific agonists that are
devoid of potentially deleterious effects mediated through activation of the 5HT2A (i.e., hallucinogenic) and 5HT2B
(i.e., cardiotoxic) subtypes. Furthermore, 5HT2C-specific agonists are required to delineate the roles of 5HT2
receptor subtypes in substance use disorders. To this end, our medicinal chemistry program has produced 4-
phenyl-2-aminotetralin (PAT) analogs with unique multifunctional pharmacology at 5HT2 GPCRs, i.e., activation
of 5HT2C signaling with inactivation of 5HT2A and 5HT2B signaling in the same monovalent, orally bioavailable,
small molecule. Our preliminary results indicate the unique PAT-type 5HT2 pharmacology translates effectively
in models of OUD in rhesus monkeys, including, attenuation of heroin-primed reinstatement, suggesting efficacy
for addressing relapse. PATs do not have stimulant or sedative effects and are without liability for addiction,
encouraging us to pursue translational studies in nonhuman primates (NHP) to guide development of PAT-type
5HT2 modulators as pharmacologic intervention for prescription and illicit opioid abuse, as well as, delineate
5HT2 roles in OUD. The overarching hypothesis tested is that an optimal balance of PAT function at 5HT2A
receptors (inverse agonism/antagonism, partial agonism) relative to agonist function at 5HT2C receptors (implicit
is no activation of 5HT2B) translates to beneficial effects in primate models of OUD. In Aim 1A medicinal chemistry
and Aim 1B molecular pharmacology studies we will develop PAT analogs with a range of functional activities,
potencies, and efficacies at 5HT2 receptors, including 5HT2C-specific agonists with 5HT2A inverse agonism. In
Aim 2A we will assess the PATs for in vivo potency and efficacy at 5HT2A and 5HT2C receptors to establish
dosing parameters for NHP studies. Aim 2B studies will use drug discrimination studies to evaluate in vivo 5HT2
activity in squirrel monkeys. Aim 3 will assess PATs for safety and efficacy to attenuate oxycodone and fentanyl
self-administration as well as drug- and cue-primed reinstatement in squirrel monkeys. Results will establish the
role of serotonergic 5HT2 receptors in the pathophysiology and pharmacotherapy of OUD. PATs that selectively
block responding for drug self-administration and have appropriate safety and efficacy parameters including with
regard to relapse will be considered for development in collateral future studies in collaboration with an identified
interested pharma.
