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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.

[Image: see text] Cortical neuron atrophy is a hallmark of depression and includes neurite retraction, dendritic spine loss, and decreased synaptic density. Psychoplastogens, small molecules capable of rapidly promoting cortical neuron growth, have been hypothesized to produce long-lasting positive effects on behavior by rectifying these deleterious structural and functional changes. Here we demonstrate that ketamine and LSD, psychoplastogens from two structurally distinct chemical classes, promote sustained growth of cortical neurons after only short periods of stimulation. Furthermore, we show that psychoplastogen-induced cortical neuron growth can be divided into two distinct epochs: an initial stimulation phase requiring TrkB activation and a growth period involving sustained mTOR and AMPA receptor activation. Our results provide important temporal details concerning the molecular mechanisms by which next-generation antidepressants produce persistent changes in cortical neuron structure, and they suggest that rapidly excreted psychoplastogens might still be effective neurotherapeutics with unique advantages over compounds like ketamine and LSD.

The marine natural product bryostatin 1 has demonstrated procognitive and antidepressant effects in animals and has been entered into human clinical trials for treating Alzheimer's disease (AD). The ability of bryostatin 1 to enhance learning and memory has largely been attributed to its effects on the structure and function of hippocampal neurons. However, relatively little is known about how bryostatin 1 influences the morphology of cortical neurons, key cells that also support learning and memory processes and are negatively impacted in AD. Here, we use a combination of carefully designed chemical probes and pharmacological inhibitors to establish that bryostatin 1 increases cortical synaptogenesis while decreasing dendritic spine density in a protein kinase C (PKC)-dependent manner. The effects of bryostatin 1 on cortical neurons are distinct from those induced by neural plasticity-promoting psychoplastogens such as ketamine. Compounds capable of increasing synaptic density with concomitant loss of immature dendritic spines may represent a unique pharmacological strategy for enhancing memory by improving signal-to-noise ratio in the central nervous system.

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 isoDMT psychoplastogens that are easier to synthesize, have improved physicochemical properties, and possess reduced hallucinogenic potential as compared to their DMT counterparts.

The myriad conformations of a G protein-coupled receptors induced by ligands are critical for determining signaling cascades associated with distinct functional and behavioral consequences. For example, 5-hydroxytryptamine 2A receptors (5-HT2AR) are the target for classic hallucinogens, atypical antipsychotics, and plasticity-promoting psychoplastogens. However, current methods are inadequate for directly assessing specific 5-HT2AR conformations. Here, we developed psychLight, a genetically-encoded fluorescent sensor based on the 5-HT2AR structure. PsychLight reports behaviorally-relevant serotonin release and 5-HT2AR conformations induced by serotonergic hallucinogens. Using a stable cell line expressing psychLight, we correctly predicted the hallucinogenic behavioral effects of compounds even with structural similarity and with previously unknown hallucinogenic potentials. We further used psychLight to identify a novel, non-hallucinogenic psychedelic analog, which promoted structural neural plasticity and produced rapid- and long-lasting antidepressant-like effects after a single administration. The advent of psychLight will enable early identification of abusive designer drugs and the development of 5-HT2AR-dependent non-hallucinogenic therapeutics.