Alexander Sherwood

• PhD
• Medicinal Chemist at Usona Institute

A general synthetic method was developed to access known tryptamine natural products present in psilocybin producing mushrooms. In vitro and in vivo experiments were then conducted to inform speculations on the psychoactive properties, or lack thereof, of the natural products. In animal models, psychedelic activity by baeocystin alone was not evide...

A second-generation kilogram-scale synthesis of the psychedelic tryptamine psilocybin has been developed. The synthesis was designed to address several challenges first encountered with the scale-up of previously described literature procedures, which were not optimized for providing consistent yield and purity of products, atom economy, or being r...

To support clinical use, a multigram-scale process has been developed to provide 5-MeO-DMT, a psychedelic natural product found in the parotid gland secretions of the toad, Incilius alvarius. Several synthetic routes were initially explored, and the selected process featured an optimized Fischer indole reaction to 5-MeO-DMT freebase in high-yield,...

Psilocybin {systematic name: 3-[2-(di­methyl­amino)­eth­yl]-1H-indol-4-yl di­hydro­gen phosphate} is a zwitterionic tryptamine natural product found in numerous species of fungi known for their psychoactive properties. Following its structural elucidation and chemical synthesis in 1959, purified synthetic psilocybin has been evaluated in clinical t...

Psilocybin, ketamine, and MDMA are psychoactive compounds that exert behavioral effects with distinguishable but also overlapping features. The growing interest in using these compounds as therapeutics necessitates preclinical assays that can accurately screen psychedelics and related analogs. We posit that a promising approach may be to measure dr...

Bipolar disorder impacts millions of patients in the United States but the mechanistic understanding of its pathophysiology and therapeutics is incomplete. Atypical antipsychotic serotonin2A (5-HT2A) receptor antagonists, such as quetiapine and olanzapine, and mood-stabilizing voltage-gated sodium channel (VGSC) blockers, such as lamotrigine, carba...

Psilocybin, ketamine, and MDMA are psychoactive compounds that exert behavioral effects with distinguishable but also overlapping features. The growing interest in using these compounds as therapeutics necessitates preclinical assays that can accurately screen psychedelics and related analogs. We posit that a promising approach may be to measure dr...

Primary metabolites of mushroom tryptamines, psilocybin and baeocystin (i.e., psilocin and norpsilocin), exhibit potent agonist activity at the serotonin 2A receptor (5-HT2A) in vitro but differ in their 5-HT2A-mediated effects in vivo. In particular, psilocin produces centrally mediated psychedelic effects in vivo, whereas norpsilocin, differing o...

Serotonergic psychedelics possess considerable therapeutic potential. Although 5-HT2A receptor activation mediates psychedelic effects, prototypical psychedelics activate both 5-HT2A-Gq/11 and β-arrestin2 transducers, making their respective roles unclear. To elucidate this, we develop a series of 5-HT2A-selective ligands with varying Gq efficacies...

Serotonergic psychedelics possess considerable therapeutic potential. Although 5-HT2A receptor activation mediates psychedelic effects, prototypical psychedelics activate both 5-HT2A-Gq/11 and β-arrestin2 signaling, making their respective roles unclear. To elucidate this, we developed a series of 5-HT2A-selective ligands with varying Gq efficacies...

A divergent two-step process has provided access to optically pure enantiomers of MDMA and MDA, clinically relevant phenylisopropylamine entactogens. Target compounds were synthesized from commercially available alanine-derived aziridines. Critical process parameters were identified, and the reactions were optimized to avoid chromatographic purific...

The Church of Psilomethoxin claims to produce a novel tryptamine by adding 5-MeO-DMT to the substrate of cultivated Psilocybe mushrooms, which is then biosynthesized into psilomethoxin, the church’s sacrament. In this study, we investigate the validity of this claim using comprehensive analytical techniques, namely ultra-performance liquid chromato...

The Church of Psilomethoxin claims to produce a novel tryptamine by adding 5-MeO-DMT to the substrate of cultivated Psilocybe mushrooms, which is then biosynthesized into psilomethoxin, the church’s sacrament. In this study, we investigate the validity of this claim using comprehensive analytical techniques, namely ultra-performance liquid chromato...

Serotonergic psychedelics are gaining increasing interest as potential therapeutics for a range of mental illnesses. Compounds with short-lived subjective effects may be clinically useful because dosing time would be reduced, which may improve patient access. One short-acting psychedelic is 5-MeO-DMT, which has been associated with improvement in d...

Introduction The clinical evaluation of hallucinogens and other small molecules, conventionally termed psychedelics, has seen a dramatic increase in the past 5 years. Several key clinical trials recently demonstrated the potential efficacy of these compounds in treating a variety of mental health conditions including depression, anxiety, and substa...

Serotonergic psychedelics are gaining increasing interest as potential therapeutics for a range of mental illnesses. Compounds with short-lived subjective effects may be clinically useful because dosing time would be reduced, which may improve patient access. One short-acting psychedelic is 5-MeO-DMT, which has been associated with improvement in d...

4-Phosphoryloxy-N,N-dimethyltryptamine (psilocybin) is a naturally occurring tertiary amine found in many mushroom species. Psilocybin is a prodrug for 4-hydroxy-N,N-dimethyltryptamine (psilocin), which induces psychedelic effects via agonist activity at the serotonin (5-HT) 2A receptor (5-HT2A). Several other 4-position ring-substituted tryptamine...

Psilocybin (1) is the major alkaloid found in psychedelic mushrooms and acts as a prodrug to psilocin (2, 4‐hydroxy‐N,N‐dimethyltryptamine), a potent psychedelic that exerts remarkable alteration of human consciousness. In contrast, the positional isomer bufotenin (7, 5‐hydroxy‐N,N‐dimethyltryptamine) differs significantly in its reported pharmacol...

The title compound, baeocystin or 4-phosphor­yloxy-N-methyl­tryptamine {systematic name: 3-[2-(methylazaniumyl)ethyl]-1H-indol-4-yl hydrogen phosphate}, C11H15N2O4P, has a single zwitterionic mol­ecule in the asymmetric unit. The mol­ecule has an intra­molecular N—H⋯O hydrogen bond between the ammonium cation and the hydro­phosphate anion. In the c...

Psilocybin, a serotonergic agonist, was granted a "breakthrough therapy" status by the Food and Drug Administration for clinical trials involving major depressive disorder and treatment-resistant depression. The direct phosphorylation of psilocin to psilocybin that uses a fast crystallization associated with a kinetically controlled process resulte...

Psilocin (1) is the dephosphorylated and psychotropic metabolite of the mushroom natural product psilocybin. Oxidation of the phenolic hydroxy group at the C‐4 position of 1 results in formation of oligomeric indoloquinoid chromophores responsible for the iconic blueing of bruised psilocybin‐producing mushrooms. Based on previous NMR experiments, t...

Background: Synthetic cathinones display overlapping behavioral effects with psychostimulants (e.g., methamphetamine; MA) and/or entactogens (e.g. 3,4-methylenedioxymethaphetamine; MDMA)-presumably reflecting their dopaminergic and/or serotonergic activity. The discriminative stimulus effects of MDMA that are thought to be mediated by such activit...

A novel analogue of psilocybin was produced by hybrid chemoenzymatic synthesis in sufficient quantity to enable bioassay. Utilizing purified 4-hydroxytryptamine kinase from Psilocybe cubensis, chemically synthesized 5-methylpsilocin (2) was enzymatically phosphorylated to provide 5-methylpsilocybin (1). The zwitterionic product was isolated from th...

The abuse of synthetic cathinones (“bath salts”) with psychomotor stimulant and/or entactogenic properties emerged as a public health concern when they were introduced as “legal” alternatives to drugs of abuse such as cocaine or MDMA. In this study, experiments were conducted in nonhuman primates to examine how differences in transporter selectivit...

Psychotropic fungi of the genus Psilocybe, colloquially referred to as „magic mushrooms”, are best known for their l‐tryptophan‐derived major natural product, psilocybin. Yet, recent research has revealed a more diverse secondary metabolism that originates from this amino acid. In this minireview, the focus is laid on l‐tryptophan and the various P...

Psilocybin, the principal indole alkaloid of Psilocybe mushrooms, is currently undergoing clinical trials as a medication against treatment‐resistant depression and major depressive disorder. The psilocybin supply for pharmaceutical purposes is met by synthetic chemistry. We replaced the problematic phosphorylation step during synthesis with the mu...

Psilocybin is a psychedelic tryptamine currently being evaluated clinically for its ability to improve the symptoms of major depressive disorder (MDD). As part of a program to fully characterize psilocybin active pharmaceutical ingredient (API) that will be used for clinical development activities, a polymorph screen involving over 150 solvent and...

Described herein is an improved synthesis of 3-[2-(dimethylamino)ethyl]-1H-indol-4-yl dihydrogen phosphate (psilocybin). The protocol outlines: synthesis of multigram quantities of psilocybin, identification of critical in-process parameters, and isolation of psilocybin without the use of chromatography, TLC, or aqueous workup. The synthesis furnis...

Psilocybin and its direct precursor baeocystin are indole alkaloids of psychotropic Psilocybe mushrooms. The pharmaceutical interest in psilocybin as a treatment option against depression and anxiety is currently being investigated in advanced clinical trials. Here, we report a biocatalytic route to synthesize 6‐methylated psilocybin and baeocystin...

5-MeO-DMT has unique pharmacology and a history of anecdotal human use suggesting potential psychotherapeutic utility. To empirically determine measures of safety and efficacy, controlled studies to support human clinical trials are necessary.

Background: Cannabinoids may be useful in the treatment of CNS disorders including drug abuse and addiction, where both CB1R antagonists / inverse agonists and CB2R agonists have shown preclinical efficacy. TV-5-249 and TV-6-41, two novel aminoalkylindoles with dual action as neutral CB1R antagonists and CB2R agonists, previously attenuated abuse-...

The use of synthetic cathinones, or “bath salts,” has become more widespread in recent years. “Bath salts” share many chemical properties with psychostimulants like methamphetamine or with entactogens like 3,4‐methylenedioxymethamphetamine (MDMA or “Ecstasy”), presumably reflecting structural differences that lead to differing neurochemical actions...

The recreational use of synthetic cathinones (“bath salts”) is a persistent public health challenge. However, there currently is a paucity of information regarding the reinforcing effects of varying types of cathinones in nonhuman primates. In this study, self‐administration of the cathinones methcathinone (MCAT), methylenedioxypyrovalerone (MDPV),...

Columbin (1) is a furanolactone diterpene isolated from the roots of Jateorhiza and Tinospora species. These species generally grow in Asia and Africa and have been used in folk medicine for their apparent analgesic and antipyretic activities. Columbin (1) is of particular interest due to its structural similarity to the known kappa-opioid receptor...

Previous structure-activity studies on the neoclerodane diterpenoid salvinorin A have demonstrated the importance of the acetoxy functionality on the A-ring in its activity as a kappa opioid receptor agonist. Few studies have focused on understanding the role of conformation in these interactions. Herein we describe the synthesis and evaluation of...

Opioids are widely used to treat millions suffering from pain, but their analgesic utility is limited due to associated side effects. Herein we report the development and evaluation of a chemical probe exhibiting analgesia and reduced opioid-induced side effects. This compound, kurkinorin (5), is a potent and selective µ-opioid receptor (MOR) agoni...

Condensation of 3,5-dimethoxyphenol with activated fluorobenzenes and subsequent demethylation provides an efficient and scalable method for the preparation of the desired structures (IV) as analogues of the cannabinoid partial agonist BAY59-3074 (V).

A variety of novel functionalized phloroglucinol monoaryl ethers have been synthesized using a two-step procedure. Target ethers were synthesized by coupling electron-deficient aryl fluorides with 3,5-dimethoxyphenol via nucleophilic aromatic substitution (SNAr) in N-methylpyrrolidone and cesium carbonate. Subsequent boron tribromide-mediated demet...

To investigate the biosynthesis of resolvins E1 and D1 (RvE1 and RvD1) in choroid-retinal endothelial cells (CRECs) and leukocytes under inflammatory conditions and to define the mechanisms of anti-inflammatory actions of RvE1 and RvD1 in CRECs and leukocytes, cells crucial to posterior ocular inflammation. RvE1, RvD1, and markers of their biosynth...

Purposes To determine the effects of choroid‐retinal endothelial cells (CREC), retinal pigment epithelial cells (RPE) and leukocytes on CREC angiogenesis including migration, vasculature formation, and proliferation. The lipid profiles in these process were also determined. Prostaglandin E2 (PGE 2 ) and 12‐hydroxy‐eicosatetraenoic acid (12‐HETE) ar...