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.
Decreased dendritic spine density in the cortex is a hallmark of several neuropsychiatric diseases, and the ability to promote cortical neuron growth has been hypothesized to underlie the rapid and sustained therapeutic effects of psychedelics. Activation of 5-hydroxytryptamine (serotonin) 2A receptors (5-HT2ARs) is essential for psychedelic-induced cortical plasticity, but it is currently unclear why some 5-HT2AR agonists promote neuroplasticity, whereas others do not. We used molecular and genetic tools to demonstrate that intracellular 5-HT2ARs mediate the plasticity-promoting properties of psychedelics; these results explain why serotonin does not engage similar plasticity mechanisms. This work emphasizes the role of location bias in 5-HT2AR signaling, identifies intracellular 5-HT2ARs as a therapeutic target, and raises the intriguing possibility that serotonin might not be the endogenous ligand for intracellular 5-HT2ARs in the cortex.
Ketamine, N,N-dimethyltryptamine (DMT), and other psychoplastogens possess enormous potential as neurotherapeutics due to their ability to potently promote neuronal growth. Here, we report the first-ever structure−activity relationship study with the explicit goal of identifying novel psychoplastogens. We have discovered several key features of the psychoplastogenic pharmacophore and used this information to develop N,N-dimethylaminoisotryptamine (isoDMT) psychoplastogens that are easier to synthesize, have improved physicochemical properties, and possess reduced hallucinogenic potential as compared to their DMT counterparts.
Azoheteroarenes make up an emerging class of photoswitchable compounds with unique photophysical properties and advantages over traditional azobenzenes. Therefore, methods for synthesizing azoheteroarenes are highly desirable. Here, we utilize azide−alkyne click chemistry to access arylazo-1,2,3triazoles, a previously unexplored class of azoheteroarenes that exhibit high thermal stabilities and near-quantitative bidirectional photoconversion. Controlling the catalyst or 1,3-dipole grants access to both regioisomeric arylazotriazoles and arylazoisoxazoles, highlighting the versatility of our approach.
Azobenzenes are widely used as dyes and photochromic compounds, with the Baeyer-Mills reaction serving as the most common method for their preparation. This transformation is often plagued by low yields...
Photoswitches capable of accessing two geometric states are highly desirable, especially if their design is modular and incorporates a pharmacophore tethering site. We describe a redox isomerization strategy for synthesizing p-formylazobenzenes from p-nitrobenzyl alcohol. The resulting azo-aldehydes can be readily converted to photoswitchable compounds with excellent photophysical properties using simple hydrazide click chemistry. As a proof of principle, we synthesized a photoswitchable surfactant enabling the photocontrol of an emulsion with exceptionally high spatiotemporal precision.
Serlyticin-A is a secondary metabolite first isolated from a culture of Serratia ureilytica grown using squid pen as the sole carbon/nitrogen source. A previous study by Kuo et al. demonstrated that it has antioxidative and antiproliferative properties. However, the proposed chemical structure of serlyticin-A is likely incorrect based on the thermodynamic instability of its three contiguous heteroatom−heteroatom bonds. Here, we use quantum chemical calculations to predict 1 H and 13 C chemical shifts for serlyticin-A and demonstrate a discrepancy between the calculated and experimental chemical shifts. We then propose several reasonable alternative structures for serlyticin-A. Considering the known antioxidant and antiproliferative activity of hydroxamic acids as well as their stability and prevalence in natural products of bacterial origin, we believe that serlyticin-A is most likely 3-indolylacetohydroxamic acid (4). We provide our rationale for this assignment as well as experimental data for pure 3-indolylacetohydroxamic acid obtained via de novo synthesis. This study highlights the power of computational NMR shift prediction to revise chemical structures for natural products like serlyticin-A.
Tryptophan, an essential amino acid, is metabolized into a variety of small molecules capable of impacting human physiology, and aberrant tryptophan metabolism has been linked to a number of diseases. There are three principal routes by which tryptophan is degraded, and thus methods for measuring metabolic flux through these pathways can be used to understand the factors that perturb tryptophan metabolism and potentially to measure disease biomarkers. Here, we describe a method utilizing 6fluorotryptophan as a probe for detecting tryptophan metabolites in ex vivo tissue samples via 19 F nuclear magnetic resonance. As a proof of concept, we demonstrate that 6-fluorotryptophan can be used to measure changes in tryptophan metabolism resulting from antibiotic-induced changes in gut microbiota composition. Taken together, we describe a general strategy for monitoring amino acid metabolism using 19 F nuclear magnetic resonance that is operationally simple and does not require chromatographic separation of metabolites.
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