A non-hallucinogenic psychedelic analogue with therapeutic potential

Abstract

The psychedelic alkaloid ibogaine has anti-addictive properties in both humans and animals. 1 Unlike most substance use disorder (SUD) medications, anecdotal reports suggest that ibogaine possesses the potential to treat patients addicted to a variety of substances including opiates, alcohol, and psychostimulants. Like other psychedelic compounds, its therapeutic effects are long-lasting, 2 which has been attributed to its ability to modify addiction-related neural circuitry through activation of neurotrophic factor signaling. 3 , 4 However, several safety concerns have hindered the clinical development of ibogaine including its toxicity, hallucinogenic potential, and proclivity for inducing cardiac arrhythmias. Here, we apply the principles of function-oriented synthesis (FOS) to identify the key structural elements of its potential therapeutic pharmacophore, enabling us to engineer tabernanthalog (TBG)—a water soluble, non-hallucinogenic, non-toxic analog of ibogaine that can be prepared in a single step. TBG promoted structural neural plasticity, reduced alcohol- and heroin-seeking behavior, and produced antidepressant-like effects in rodents. This work demonstrates that through careful chemical design, it is possible to modify a psychedelic compound to produce a safer, non-hallucinogenic variant with therapeutic potential.

Psychedelic-inspired drug discovery using an engineered biosensor

“…PsychLight can be used to identify non-hallucinogenic 5-HT2AR antagonists (e.g., antipsychotics like clozapine) or non-hallucinogenic biased agonists (e.g., LIS). Non-hallucinogenic psychoplastogens have emerged as an incredibly exciting class of 5-HT2AR ligands given the broad implications that neural plasticity-promoting compounds have for treating a variety of brain disorders (Cameron et al, 2021;Dunlap et al, 2020). We used psychLight to identify AAZ-A-154-a non-hallucinogenic analog of a psychedelic compound occupying previously unknown chemical space that promotes neuronal growth and produces long-lasting (>2-week) beneficial behavioral effects in rodents following a single administration.…”

“…Given its similar structure to several known psychoplastogens (Ly et al, 2018), we tested the ability of AAZ-A-154 to promote dendritic outgrowth in cultured rat embryonic cortical neurons (Cameron et al, 2021;Dunlap et al, 2020). Treatment with AAZ-A-154 increases dendritic arbor complexity to a comparable extent as the fast-acting antidepressant ketamine (KET) (Figures 6A and 6B).…”

“…Like ketamine, psychedelics promote neural plasticity in key circuits relevant to mood, fear, and reward (Ly et al, 2018). Recent rodent studies using sub-hallucinogenic doses (Cameron et al, 2019) and non-hallucinogenic congeners (Cameron et al, 2021) suggest that the hallucinogenic effects of 5-HT2AR ligands may not be necessary to promote neural plasticity and produce therapeutic outcomes. Thus, there is a critical need to develop methods for reliably determining if a novel ligand is likely to induce hallucinogen-specific conformations of the 5-HT2AR.…”

Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans

“…The less toxic ibogaine ( 17 ) congener 18-methoxycoronaridine ( 19 ) is likewise a putative anti-addictive compound, apparently due to its antagonism at α 3 β 4 nicotinic acetylcholine receptors [ 64 ]. Tabernanthalog ( 20 ) and a series of other ibogaine ( 17 ) analogues lacking the isoquinuclidine retained the capacity to promote synaptic plasticity, while being much less cardiotoxic and teratogenic than ibogaine ( 17 ) itself [ 65 ].…”

Comparative Analysis of Pathobiochemical Changes in Major Depression and Post-Traumatic Stress Disorder

“…However, the efficiency of antidepressants remains low and frequently is different from that of placebo only in the cases of severe depression [77]. To affect neuro plasticity more selectively and without side effects inher ent for the existent monoamine antidepressants, a new class of therapeutics, "psychoplastogens", is being devel oped [78].…”