Psychedelic-inspired drug discovery using an engineered biosensor.

Ligands can induce G protein-coupled receptors (GPCRs) to adopt a myriad of conformations, many of which play critical roles in determining the activation of specific signaling cascades associated with distinct functional and behavioral consequences. For example, the 5-hydroxytryptamine 2A receptor (5-HT2AR) is the target of classic hallucinogens, atypical antipsychotics, and psychoplastogens. However, currently available methods are inadequate for directly assessing 5-HT2AR conformation both in vitro and in vivo. Here, we developed psychLight, a genetically encoded fluorescent sensor based on the 5-HT2AR structure. PsychLight detects behaviorally relevant serotonin release and correctly predicts the hallucinogenic behavioral effects of structurally similar 5-HT2AR ligands. We further used psychLight to identify a non-hallucinogenic psychedelic analog, which produced rapid-onset and long-lasting antidepressant-like effects after a single administration. The advent of psychLight will enable in vivo detection of serotonin dynamics, early identification of designer drugs of abuse, and the development of 5-HT2AR-dependent non-hallucinogenic therapeutics.

Directed Evolution of a Selective and Sensitive Serotonin Sensor via Machine Learning.

Serotonin plays a central role in cognition and is the target of most pharmaceuticals for psychiatric disorders. Existing drugs have limited efficacy; creation of improved versions will require better understanding of serotonergic circuitry, which has been hampered by our inability to monitor serotonin release and transport with high spatial and temporal resolution. We developed and applied a binding-pocket redesign strategy, guided by machine learning, to create a high-performance, soluble, fluorescent serotonin sensor (iSeroSnFR), enabling optical detection of millisecond-scale serotonin transients. We demonstrate that iSeroSnFR can be used to detect serotonin release in freely behaving mice during fear conditioning, social interaction, and sleep/wake transitions. We also developed a robust assay of serotonin transporter function and modulation by drugs. We expect that both machine-learning-guided binding-pocket redesign and iSeroSnFR will have broad utility for the development of other sensors and in vitro and in vivo serotonin detection, respectively.

The Effects of Psychedelics on Neuronal Physiology.

Psychedelics are quite unique among drugs that impact the central nervous system, as a single administration of a psychedelic can both rapidly alter subjective experience in profound ways and produce sustained effects on circuits relevant to mood, fear, reward, and cognitive flexibility. These remarkable properties are a direct result of psychedelics interacting with several key neuroreceptors distributed across the brain. Stimulation of these receptors activates a variety of signaling cascades that ultimately culminate in changes in neuronal structure and function. Here, we describe the effects of psychedelics on neuronal physiology, highlighting their acute effects on serotonergic and glutamatergic neurotransmission as well as their long-lasting effects on structural and functional neuroplasticity in the cortex. We propose that the neurobiological changes leading to the acute and sustained effects of psychedelics might be distinct, which could provide opportunities for engineering compounds with optimized safety and efficacy profiles.

A non-hallucinogenic psychedelic analogue with therapeutic potential.

The psychedelic alkaloid ibogaine has anti-addictive properties in both humans and animals1. Unlike most medications for the treatment of substance use disorders, anecdotal reports suggest that ibogaine has the potential to treat addiction to various substances, including opiates, alcohol and psychostimulants. The effects of ibogaine-like those of other psychedelic compounds-are long-lasting2, which has been attributed to its ability to modify addiction-related neural circuitry through the activation of neurotrophic factor signalling3,4. However, several safety concerns have hindered the clinical development of ibogaine, including its toxicity, hallucinogenic potential and tendency to induce cardiac arrhythmias. Here we apply the principles of function-oriented synthesis to identify the key structural elements of the potential therapeutic pharmacophore of ibogaine, and we use this information to engineer tabernanthalog-a water-soluble, non-hallucinogenic, non-toxic analogue of ibogaine that can be prepared in a single step. In rodents, tabernanthalog was found to promote structural neural plasticity, reduce alcohol- and heroin-seeking behaviour, and produce antidepressant-like effects. This work demonstrates that, through careful chemical design, it is possible to modify a psychedelic compound to produce a safer, non-hallucinogenic variant that has therapeutic potential.

Psychedelics and Neural Plasticity: Therapeutic Implications.

Psychedelic drugs have reemerged as tools to treat several brain disorders. Cultural attitudes toward them are changing, and scientists are once again investigating the neural mechanisms through which these drugs impact brain function. The significance of this research direction is reflected by recent work, including work presented by these authors at the 2022 meeting of the Society for Neuroscience. As of 2022, there were hundreds of clinical trials recruiting participants for testing the therapeutic effects of psychedelics. Emerging evidence suggests that psychedelic drugs may exert some of their long-lasting therapeutic effects by inducing structural and functional neural plasticity. Herein, basic and clinical research attempting to elucidate the mechanisms of these compounds is showcased. Topics covered include psychedelic receptor binding sites, effects of psychedelics on gene expression, and on dendrites, and psychedelic effects on microcircuitry and brain-wide circuits. We describe unmet clinical needs and the current state of translation to the clinic for psychedelics, as well as other unanswered basic neuroscience questions addressable with future studies.

Synthetic Strategies toward Lysergic Acid Diethylamide: Ergoline Synthesis via α-Arylation, Borrowing Hydrogen Alkylation, and C-H Insertion.

Lysergic acid diethylamide (LSD), a semisynthetic ergoline alkaloid analogue and hallucinogen, is a potent psychoplastogen with promising therapeutic potential. While a variety of synthetic strategies for accessing ergoline alkaloids have emerged, the complexity of the tetracyclic ring system results in distinct challenges in preparing analogues with novel substitution patterns. Methods of modulating the hallucinogenic activity of LSD by functionalization at previously inaccessible positions are of continued interest, and efficient syntheses of the ergoline scaffold are integral toward this purpose. Here, we report novel C-C bond forming strategies for preparing the ergoline tetracyclic core, focusing on the relatively unexplored strategy of bridging the B- and D-ring systems last. Following cross-coupling to first join the A- and D-rings, we explored a variety of methods for establishing the C-ring, including intramolecular α-arylation, borrowing hydrogen alkylation, and rhodium-catalyzed C-H insertion. Our results led to a seven-step formal synthesis of LSD and the first methods for readily introducing substitution on the C-ring. These strategies are efficient for forming ergoline-like tetracyclic compounds and analogues, though they each face unique challenges associated with elaboration to ergoline natural products. Taken together, these studies provide important insights that will guide future synthetic strategies toward ergolines.

Biochemical Mechanisms Underlying Psychedelic-Induced Neuroplasticity.

In addition to producing profound subjective effects following acute administration, psychedelic compounds can induce beneficial behavioral changes relevant to the treatment of neuropsychiatric disorders that last long after the compounds have been cleared from the body. One hypothesis with the potential to explain the remarkable enduring effects of psychedelics is related to their abilities to promote structural and functional neuroplasticity in the prefrontal cortex (PFC). A hallmark of many stress-related neuropsychiatric diseases, including depression, post-traumatic stress disorder (PTSD), and addiction, is the atrophy of neurons in the PFC. Psychedelics appear to be particularly effective catalysts for the growth of these key neurons, ultimately leading to restoration of synaptic connectivity in this critical brain region. Furthermore, evidence suggests that the hallucinogenic effects of psychedelics are not directly linked to their ability to promote structural and functional neuroplasticity. If we are to develop improved alternatives to psychedelics for treating neuropsychiatric diseases, we must fully characterize the molecular mechanisms that give rise to psychedelic-induced neuroplasticity. Here, I review our current understanding of the biochemical signaling pathways activated by psychedelics and related neuroplasticity-promoting molecules, with an emphasis on key unanswered questions.

Psychedelic-inspired approaches for treating neurodegenerative disorders.

Psychedelics are increasingly being recognized for their potential to treat a wide range of brain disorders including depression, post-traumatic stress disorder (PTSD), and substance use disorder. Their broad therapeutic potential might result from an ability to rescue cortical atrophy common to many neuropsychiatric and neurodegenerative diseases by impacting neurotrophic factor gene expression, activating neuronal growth and survival mechanisms, and modulating the immune system. While the therapeutic potential of psychedelics has not yet been extended to neurodegenerative disorders, we provide evidence suggesting that approaches based on psychedelic science might prove useful for treating these diseases. The primary target of psychedelics, the 5-HT2A receptor, plays key roles in cortical neuron health and is dysregulated in Alzheimer's disease. Moreover, evidence suggests that psychedelics and related compounds could prove useful for treating the behavioral and psychological symptoms of dementia (BPSD). While more research is needed to probe the effects of psychedelics in models of neurodegenerative diseases, the robust effects of these compounds on structural and functional neuroplasticity and inflammation clearly warrant further investigation.

An analog of psychedelics restores functional neural circuits disrupted by unpredictable stress.

Psychological stress affects a wide spectrum of brain functions and poses risks for many mental disorders. However, effective therapeutics to alleviate or revert its deleterious effects are lacking. A recently synthesized psychedelic analog tabernanthalog (TBG) has demonstrated anti-addictive and antidepressant potential. Whether TBG can rescue stress-induced affective, sensory, and cognitive deficits, and how it may achieve such effects by modulating neural circuits, remain unknown. Here we show that in mice exposed to unpredictable mild stress (UMS), administration of a single dose of TBG decreases their anxiety level and rescues deficits in sensory processing as well as in cognitive flexibility. Post-stress TBG treatment promotes the regrowth of excitatory neuron dendritic spines lost during UMS, decreases the baseline neuronal activity, and enhances whisking-modulation of neuronal activity in the somatosensory cortex. Moreover, calcium imaging in head-fixed mice performing a whisker-dependent texture discrimination task shows that novel textures elicit responses from a greater proportion of neurons in the somatosensory cortex than do familiar textures. Such differential response is diminished by UMS and is restored by TBG. Together, our study reveals the effects of UMS on cortical neuronal circuit activity patterns and demonstrate that TBG combats the detrimental effects of stress by modulating basal and stimulus-dependent neural activity in cortical networks.

The iboga enigma: the chemistry and neuropharmacology of iboga alkaloids and related analogs.

Covering: 2000 up to 2020 Few classes of natural products have inspired as many chemists and biologists as have the iboga alkaloids. This family of monoterpenoid indole alkaloids includes the anti-addictive compound ibogaine as well as catharanthine, a precursor to the chemotherapeutic vinblastine. Despite being known for over 120 years, these small molecules continue to challenge our assumptions about biosynthetic pathways, catalyze our creativity for constructing complex architectures, and embolden new approaches for treating mental illness. This review will cover recent advances in both the biosynthesis and chemical synthesis of iboga alkaloids as well as their use as next-generation neurotherapeutics. Whenever appropriate, we provide historical context for the discoveries of the past decade and indicate areas that have yet to be resolved. While significant progress regarding their chemistry and pharmacology has been made since the 1960s, it is clear that the iboga alkaloids will continue to stoke scientific innovation for years to come.

Calculated oxidation potentials predict reactivity in Baeyer-Mills reactions.

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 due to the formation of undesired azoxybenzene. Here, we explore electronic effects dictating the formation of the azoxybenzene side-product. Using calculated oxidation potentials, we were able to predict reaction outcomes and improve reaction efficiency simply by modulating the oxidation potential of the arylamine component.

Reconsidering the Structure of Serlyticin-A.

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 1H and 13C 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.

Synthetic Studies Toward Pactamycin Highlighting Oxidative C-H and Alkene Amination Technologies.

A strategy enabled by C-H and alkene amination technologies for synthesizing the aminocyclitol natural product, pactamycin, is disclosed. This work features two disparate approaches for assembling the five-membered ring core of the target, the first of which utilizes acyl anion catalysis and a second involving ß-ketoester aerobic hydroxylation. Installation of the C3-N bond, one of three contiguous nitrogen centers, is made possible through Rh-catalyzed allylic C-H amination of a sulfamate ester. Subsequent efforts are presented to introduce the C1,C2 cis-diamino moiety en route to pactamycin, including carbamate-mediated alkene aziridination. In the course of these studies, assembly of the core of C2- epi-pactamycate, which bears the carbon skeleton and all of the requisite nitrogen and oxygen functional groups found in the natural product, has been achieved.

Hydroxamic acid-based histone deacetylase (HDAC) inhibitors can mediate neuroprotection independent of HDAC inhibition.

Histone deacetylase (HDAC) inhibition improves function and extends survival in rodent models of a host of neurological conditions, including stroke, and neurodegenerative diseases. Our understanding, however, of the contribution of individual HDAC isoforms to neuronal death is limited. In this study, we used selective chemical probes to assess the individual roles of the Class I HDAC isoforms in protecting Mus musculus primary cortical neurons from oxidative death. We demonstrated that the selective HDAC8 inhibitor PCI-34051 is a potent neuroprotective agent; and by taking advantage of both pharmacological and genetic tools, we established that HDAC8 is not critically involved in PCI-34051's mechanism of action. We used BRD3811, an inactive ortholog of PCI-34051, and showed that, despite its inability to inhibit HDAC8, it exhibits robust neuroprotective properties. Furthermore, molecular deletion of HDAC8 proved insufficient to protect neurons from oxidative death, whereas both PCI-34051 and BRD3811 were able to protect neurons derived from HDAC8 knock-out mice. Finally, we designed and synthesized two new, orthogonal negative control compounds, BRD9715 and BRD8461, which lack the hydroxamic acid motif and showed that they stably penetrate cell membranes but are not neuroprotective. These results indicate that the protective effects of these hydroxamic acid-containing small molecules are likely unrelated to direct epigenetic regulation via HDAC inhibition, but rather due to their ability to bind metals. Our results suggest that hydroxamic acid-based HDAC inhibitors may mediate neuroprotection via HDAC-independent mechanisms and affirm the need for careful structure-activity relationship studies when using pharmacological approaches.

Heat Illness in Football: Current Concepts.

Despite growing health and safety concerns, American football remains a vastly popular sport in the United States. Unfortunately, even with increased efforts in promoting education and hydration, the incidence of death from exertional heat stroke continues to rise. General risk factors such as hydration status, obesity, fitness level, and football-specific risk factors such as timing of training camp and equipment all contribute to the development of heat illness. At the professional level, changes have been made to effectively reduce mortality from heat stroke with no deaths since August 2001. However, there have been at least 33 total deaths at the high school and collegiate levels since this time. More efforts need to be focused at these levels to mandate exertional heat illness prevention guidelines in order to reverse this trend of mortality in our younger athletes.

Vicinal diamination of alkenes under Rh-catalysis.

The synthesis of 1,2-diamines has been achieved through a single-step, tandem sequence involving Rh-catalyzed aziridination followed by NaI-promoted rearrangement to an isomeric cyclic sulfamide. Facile ring opening of these products in hot water and pyridine affords differentially protected vicinal diamines. Demonstration of the utility of this method for the syntheses of (±)-enduracididine and (±)-allo-enduracididine is highlighted.

Therapeutic mechanisms of psychedelics and entactogens.

Recent clinical and preclinical evidence suggests that psychedelics and entactogens may produce both rapid and sustained therapeutic effects across several indications. Currently, there is a disconnect between how these compounds are used in the clinic and how they are studied in preclinical species, which has led to a gap in our mechanistic understanding of how these compounds might positively impact mental health. Human studies have emphasized extra-pharmacological factors that could modulate psychedelic-induced therapeutic responses including set, setting, and integration-factors that are poorly modelled in current animal experiments. In contrast, animal studies have focused on changes in neuronal activation and structural plasticity-outcomes that are challenging to measure in humans. Here, we describe several hypotheses that might explain how psychedelics rescue neuropsychiatric disease symptoms, and we propose ways to bridge the gap between human and rodent studies. Given the diverse pharmacological profiles of psychedelics and entactogens, we suggest that their rapid and sustained therapeutic mechanisms of action might best be described by the collection of circuits that they modulate rather than their actions at any single molecular target. Thus, approaches focusing on selective circuit modulation of behavioral phenotypes might prove more fruitful than target-based methods for identifying novel compounds with rapid and sustained therapeutic effects similar to psychedelics and entactogens.

Identification of Psychoplastogenic Tropanes Lacking Muscarinic Activity.

Tropane-containing small molecules like scopolamine are a promising class of psychoplastogens. However, their potent antagonism of all muscarinic receptor subtypes presents the potential for undesirable anticholinergic side effects. In an effort to decouple their neuroplasticity-promoting effects from their muscarinic activity, we performed phenotypic structure-activity relationship studies across a variety of structurally distinct subclasses of tropanes. We discovered several novel tropanes capable of significantly increasing cortical neuronal growth while exhibiting drastically reduced activity at all muscarinic receptor subtypes compared to scopolamine.

Psychoplastogenic DYRK1A Inhibitors with Therapeutic Effects Relevant to Alzheimer's Disease.

Tauopathy, neuronal atrophy, and psychological impairments are hallmarks of neurodegenerative diseases, such as Alzheimer's disease, that currently lack efficacious clinical treatments capable of rectifying these issues. To address these unmet needs, we used rational drug design to combine the pharmacophores of DYRK1A inhibitors and isoDMTs to develop psychoplastogenic DYRK1A inhibitors. Using this approach, we discovered a nonhallucinogenic compound capable of promoting cortical neuron growth and suppressing tau hyperphosphorylation while also having the potential to mitigate the biological and psychological symptoms of dementia. Together, our results suggest that hybridization of the DYRK1A and psychoplastogen pharmacophores represents a promising strategy for identifying compounds that might address the cognitive as well as the behavioral and psychological symptoms of dementia.