Serotonin 2A receptor (5-HT2AR) agonists and κ-opioid receptor (KOR) agonists have been demonstrated to be effective treatments for several Central Nervous System (CNS) disorders including depression, anxiety, addiction, and pain. In a recent clinical study, psilocybin (a classical hallucinogen) has been shown to significantly decrease the depressive symptoms of Major Depressive Disorder (MDD) and Treatment Resistance Depression (TRD) in humans for up to six weeks after a single dose.1 Several KOR agonists have been shown to be effective treatments of chronic pain without the physical dependence risks of µ-opioid receptor agonists.2 Also, due to KOR’s involvement in a biological anti-reward system, agonists for this receptor possess anti-addiction properties as demonstrated by their ability to decrease the self-administration of drugs of abuse in multiple different animal species.3 Despite the great therapeutic potential for both these classes of molecules, their hallucinogenic and disassociate effects have been a major roadblock in the approval new pharmaceuticals.
I will present two collaborative projects from the Sames Lab which involve the synthesis and behavioral evaluation of novel derivatives of psychedelic molecules with the goal of introducing efficacious therapeutics with a lower side-effect profile. In the first, I introduce the “oxa-iboga” class which was synthesized based on the structure of Ibogaine, a natural product with antiaddictive properties. Notably, one of the molecules in this class, oxa-noribogaine, is a potent KOR agonist and analgesic, but has a lower side-effect profile compared to other iboga alkaloids.4 In the second, I will discuss a set of substituted phenethylamines which act as 5-HT2AR agonists, and had their hallucinogenic and anti-depressant effects investigated in mouse models.