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Synthesis, Structural Characterization, and PharmacologicalActivity of Novel Quaternary Salts of 4-Substituted Tryptamines

Grant C Glatfelter†,*,Duyen N K Pham‡,Donna Walther†,James A Golen‡,Andrew R Chadeayne§,Michael H Baumann†,David R Manke‡,*
†DesignerDrug Research Unit, National Institute onDrug Abuse, Intramural Research Program, Baltimore, Maryland 21224 United States
‡Departmentof Chemistry and Biochemistry, Universityof Massachusetts Dartmouth, North Dartmouth, Massachusetts 02747, United States
§CaaMTech,Inc., Issaquah, Washington 98027, United States
*

Email:grant.glatfelter@nih.gov.

*

Email:dmanke@umassd.edu.

Collection date 2022 Jul 19.

© 2022 The Authors. Published by American Chemical Society

Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).

PMCID: PMC9301952  PMID:35874244

Abstract

graphic file with name ao2c03476_0005.jpg

Aeruginascin (4-phosphoryloxy-N,N,N-trimethyltryptammonium)is an analogue of psilocybin(4-phosphoryloxy-N,N-dimethyltryptamine)that has been identified in several species of psilocybin-containingmushrooms. Our team previously reported the synthesis, structuralcharacterization, and biological activity of the putative metaboliteof aeruginascin (4-hydroxy-N,N,N-trimethyltryptammonium; 4-HO-TMT) and its potential prodrug(4-acetoxy-N,N,N-trimethyltryptammonium; 4-AcO-TMT). Here, we report the synthesis,structural characterization, and pharmacological activity of severalquaternary tryptammonium analogues of 4-HO-TMT and 4-AcO-TMT, namely,4-hydroxy-N,N-dimethyl-N-ethyltryptammonium (4-HO-DMET), 4-hydroxy-N,N-dimethyl-N-n-propyltryptammonium(4-HO-DMPT), and 4-hydroxy-N,N-dimethyl-N-isopropyltryptammonium (4-HO-DMiPT), as well as theirhypothesized prodrugs 4-acetoxy-N,N-dimethyl-N-ethyltryptammonium (4-AcO-DMET), 4-acetoxy-N,N-dimethyl-N-n-propyltryptammonium (4-AcO-DMPT), and 4-acetoxy-N,N-dimethyl-N-isopropyltryptammonium(4-AcO-DMiPT). Compounds were synthesized using established methods,and structures were characterized by single-crystal X-ray diffraction.Test compounds were screened for in vitro pharmacological activityat a variety of receptors and transporters to determine potentialtargets of action. None of the compounds exhibited measurable affinityfor the serotonin 2A receptor (5-HT2A), but several analogueshad low micromolar affinity (Ki) for theserotonin 1D receptor (5-HT1D) and serotonin 2B receptor(5-HT2B), where they appeared to be weak partial agonistswith low micromolar potencies. Importantly, 4-HO-DMET, 4-HO-DMPT,and 4-HO-DMiPT displayed sub-micromolar affinity for the serotonintransporter (SERT; 370–890 nM). The same 4-hydroxy analogueshad low to sub-micromolar potencies (IC50) for inhibitionof 5-HT uptake at SERT in transfected cells (3.3–12.3 μM)and rat brain tissue (0.31–3.5 μM). Overall, our resultsshow that quaternary tryptammonium analogues do not target 5-HT2A sites, suggesting the compounds lack psychedelic-like subjectiveeffects. However, certain 4-hydroxy quaternary tryptammonium analoguesmay provide novel templates for exploring structure–activityrelationships for selective actions at SERT.

Introduction

Emerging clinical evidencesuggests that psychedelics, such aspsilocybin (4-phosphoryloxy-N,N-dimethyltryptamine),have therapeutic potential in treating various psychiatric disorders.1−5 Psychedelics interact with a number of G protein-coupled receptorsin preclinical models, but the primary subjective effects of psychedelicsin humans seem to be mediated by agonist actions at the serotonin2A receptor (5-HT2A).2,6 Whether the acute subjectiveeffects of psychedelics are related to their long-term therapeuticattributes is still unresolved, but the current interest in psychedelicsprovides unique opportunities for medication development. To thisend, the basic structures of psilocybin and related tryptamine compoundsare amenable to structure–activity relationship (SAR) studiesthat could identify candidate medications for treating specific diseases.

Hallucinogenic mushrooms containing psilocybin are known to containother tryptamines with unexplored biological activity.7 Norbaeocystin (4-phosphoryloxytryptamine), baeocystin (4-phosphoryloxy-N-methyltryptamine), norpsilocin (4-hydroxy-N-methyltryptamine), and aeruginascin (4-phosphoryloxy-N,N,N-trimethyltryptammonium) aresome of the tryptamines structurally related to psilocybin and itsactive metabolite, psilocin (4-hydroxy-N,N-dimethyltryptamine), found in psilocybin-containing mushrooms.8−12 The pharmacological activities of baeocystin and norpsilocin wererecently studied by Sherwood et al., who showed that neither compoundis active in the mouse head twitch assay, a behavioral assay usedto predict psychedelic drug activity.7,13 Biologicaleffects of the quaternary ammonium analogue of psilocybin—aeruginascin(Figure1)—havenot been explored, despite reports of enhanced psychedelic-like subjectiveeffects after consumption ofInocybe aeruginascens, which contains aeruginascin and psilocybin.11,12 Aeruginascin also appears to be one of a few tryptamines found inPsilocybe cubensis, a popular species of hallucinogenicmushroom used recreationally and as a religious sacrament.14

Figure 1.

Figure 1

Structures of aeruginascin as well as putative activemetabolite,synthetic prodrug, and novel derivatives thereof included in the study.

In the present study, we describe the synthesisand structuralcharacterization of analogues of the hydrolysis product of aeruginascin,as well as potential prodrugs for these molecules (Figure1 andFigure2). Members of our team have previously publishedthe structural characterization and serotonergic receptor bindingaffinities of the putative active metabolite of aeruginascin (4-hydroxy-N,N,N-trimethyltryptammonium;4-HO-TMT) and its potential prodrug (4-acetoxy-N,N,N-trimethyltryptammonium; 4-AcO-TMT).15 Here, we report the in vitro pharmacologicalactivity of six novel analogues of 4-HO-TMT and 4-AcO-TMT. We foundthat none of the compounds display measurable affinity for 5-HT2A, but some of the compounds have low micromolar affinity(i.e.,Ki) for the serotonin 1D receptor(5-HT1D) and the serotonin 2B receptor (5-HT2B), as well as sub-micromolar affinity at the serotonin transporter(SERT). These affinities translated to weak partial agonist activitiesat 5-HT1D and 5-HT2B receptors. Further, compoundswere moderate uptake blockers in SERT assays but not dopamine transporter(DAT) assays.

Figure 2.

Figure 2

Crystal structures of the aeruginascin active metabolite4-HO-TMT,synthetic prodrug 4-AcO-TMT, and novel derivatives thereof includedin the study.

Results and Discussion

Synthesis of AeruginascinAnalogues

The synthesis ofthe putative metabolite of aeruginascin (4-HO-TMT) and its potentialprodrug (4-AcO-TMT) were reported previously.15 Six new compounds were prepared by procedures modified from thosein the prior report. The 4-acetoxy prodrug derivatives (4-AcO-DMET,4-AcO-DMPT, 4-AcO-DMiPT) were synthesized by refluxing excess alkyliodide (iodoethane, 1-iodopropane, 2-iodopropane) in a tetrahydrofuransolution of psilacetin (4-acetoxy-N,N,-dimethyltryptamine; 4-AcO-DMT). The prodrug derivatives were hydrolyzedto their corresponding metabolite analogues (4-HO-DMET, 4-HO-DMPT,4-HO-DMiPT) by refluxing them in a 5:1 acetic acid/water solution.Detailed syntheses and characterization of all compounds are containedin theSupporting Information.

StructuralCharacterization of Aeruginascin Analogues

All compoundswere structurally characterized by single-crystal X-raydiffraction. All operations were performed on a Bruker D8 VentureCMOS diffractometer, using Mo Kα radiation with a TRIUMPH monochromator.Details of data collection, refinement, and structural parametersare contained in theSupporting Information. Files can be obtained from the Cambridge Crystallographic DatabaseCentre (CCDC 2123853–2123858). The structures of only fivequaternary tryptammonium compounds have been reported previously.15−18

Pharmacological Activity of Aeruginascin Analogues

All compoundswere tested for in vitro activity by the National Instituteof Mental Health, Psychoactive Drug Screening Program (NIMH PDSP).The initial primary screening used a fixed concentration of each testcompound (10 μM) to detect inhibition of radioligand bindingat 46 different pharmacological targets.19 Follow-up secondary screening, which provided dose–responsecurves andKi affinity values, was carriedout for those compounds exhibiting >50% inhibition of radioligandbinding in the 10 μM primary screens (Table1).

Table 1. Pharmacological TargetProfiles andBinding Affinity of Quaternary Salts of 4-Substituted Tryptaminesat Identified Human 5-HT Receptors and Monoamine Transporters.

compoundtargets identified in 10 μM PDSP screena5-HT1DKi (μM)5-HT2BKi (μM)DATKi (μM)SERTKi (μM)
  [3H]GR125743[3H]LSD[3H]WIN35428[3H]citalopram
4-HO-TMTDAT, 5-HT2B, 5-HT1D4.861.287.92 
4-AcO-TMTDAT, 5-HT2B 1.174.35 
4-HO-DMPTDAT, SERT, 5-HT2B, 5-HT1D2.381.098.750.83
4-HO-DMETSERT, 5-HT2B 1.35 0.89
4-HO-DMiPTSERT   0.37
4-AcO-DMPTnone    
4-AcO-DMETDAT  >10 
4-AcO-DMiPTDAT  >10 
a

Targets that exhibited >50% averageinhibition. Ergotamine tartrateKi valueat 5-HT1D = 2.97 nM. SB 206553Ki value at 5-HT2B = 4.86 nM. GBR 12909Ki value at DAT = 2.89 nM. AmitriptylineKi value at SERT = 6.36 nM.

Primary screening at monoamine transporters revealedthat 4-HO-TMT,4-AcO-TMT, 4-HO-DMPT, 4-AcO-DMET, and 4-AcO-DMiPT competed for radioligandbinding at DAT, while 4-HO-DMPT, 4-HO-DMET, and 4-HO-DMiPT competedfor radioligand binding at SERT. Primary screening also revealed that4-HO-TMT, 4-AcO-TMT, 4-HO-DMPT, and 4-HO-DMET competed for radioligandbinding at 5-HT2B, while 4-HO-TMT and 4-HO-DMPT also competedat 5-HT1D. Notably, 4-AcO-DMiPT displayed no inhibitionof radioligand binding >50% at any of the 46 sites tested. 4-HO-DMPTinhibited >50% of specific radioligand binding at the greatestnumberof sites (4) at the 10 μM primary screening concentration.

Interestingly, primary screens showed no inhibition of bindingto 5-HT2A or the serotonin 1A receptor (5-HT1A) for any of the compounds, in contrast to our previous study whichshowed 4-HO-TMT had micromolar affinity for these sites.15 The discrepancy between 5-HT2A bindingresults in previous experiments versus the present work could be explainedby the use of an agonist radioligand ([125I]DOI) in theprior report versus an antagonist radioligand ([3H]ketanserin)in the current work. It is well-established that the specific radioligandused for labeling receptor proteins can markedly influence the measuredaffinity of competing test compounds.20−26 However, it has also been shown that affinity for psychedelics tocompete for [3H]ketanserin binding correlates with theirpsychoactive dose in humans.27 Becausenone of the tryptammonium analogues inhibited radioligand bindingat 5-HT2A, we hypothesize that these compounds may lackpsychedelic effects in vivo.13

Radioligandsused for secondary screening,Ki valuesfor each test compound, and the cold ligand comparatorKi values are listed inTable1. Secondary screening results revealed thatthe only sub-micromolarKi values wereat SERT. More specifically, 4-HO-DMPT, 4-HO-DMET, and 4-HO-DMiPT alldisplayed sub-micromolar affinity for SERT labeled with [3H]citalopram (370–890 nM;Table1). 4-HO-TMT and 4-HO-DMPT had affinitiesof 4.9 and 2.4 μM for 5-HT1D labeled with [3H]GR125743 (Table1). Furthermore, 4-HO-TMT, 4-AcO-TMT, 4-HO-DMPT, and 4-HO-DMET alldisplayed affinity for [3H]LSD-labeled 5-HT2B (Ki = 1.1–1.4 μM;Table1). Results for 4-HO-TMTand 4-AcO-TMT at 5-HT2B are at odds with previous experimentsshowing that these compounds had affinities of 120 and >10,000nMfor displacement of [125I]DOI binding at 5-HT2B, respectively.15 Here, we show that bothcompounds compete for [3H]LSD binding to 5-HT2B with low micromolar affinity. Discrepancies in the data likely resultfrom differences in radioligand used and assay conditions employed.25,26 For [3H]WIN35428 binding, 4-HO-TMT, 4-AcO-TMT, and 4-HO-DMPT(4.3–8.7 μM), but not 4-AcO-DMET or 4-AcO-DMiPT (>10μM), displayed affinity for DAT, demonstrating the relevanceof acetoxy versus hydroxy substitution at the 4-position (Table1). Lastly, the radioligandbinding assays did not identify any other pharmacological activitiesfor 4-HO-DMiPT except for SERT, indicating that this compound maybe selective for that site.

Substitution of an acetoxy for ahydroxy at the 4-position reducedaffinity at the four identified binding sites (5-HT1D,5-HT2B, DAT, SERT). Of the acetoxy esters tested, only4-AcO-TMT displayed any binding affinity, withKi values of 1.17 and 4.35 μM at 5-HT2B andDAT, respectively, and showed competition for binding at 5-HT1D unlike its 4-hydroxy counterpart (Table1). These observations are consistent withprevious suggestions that 4-phosphoryloxytryptamine prodrugs (e.g.,psilocybin) have reduced pharmacological activity compared to theirhydrolyzed 4-hydroxy analogues (e.g., psilocin), which are generallyconsidered the active metabolites of 4-phosphoryloxy and 4-acetoxyanalogues.7,28 The three 4-hydroxy compounds with the loweststeric bulk about their quaternary nitrogens, and 4-AcO-TMT, all competedfor radioligand binding at 5-HT2B withKi values around 1 μM. Three of these compounds (4-HO-TMT,4-HO-DMPT, and 4-AcO-TMT) showed modest binding affinity at DAT. Mostnotably, increasing the steric bulk about the quaternary nitrogenafforded increased binding at the SERT. The smallest 4-hydroxy compound(4-HO-TMT) showed no competition for radioligand binding at SERT.Increasing the bulk at the quaternary nitrogen by incorporating linearalkyl chains, ethyl (4-HO-DMET) andn-propyl (4-HO-DMPT),engendered increased affinity at SERT, with similarKi values of 830 and 890 nM, respectively (Table1). Finally, incorporating abranched alkyl chain with a tertiary carbon at the nitrogen, isopropyl(4-HO-DMiPT), further improved SERT binding affinity, showing aKi of 370 nM (Table1). The steric impact of the quaternary ammoniumis an interesting SAR at SERT, with an increase in steric bulk demonstratingimproved competition for radioligand binding at this target. Conversely,increasing the steric bulk seems to weaken binding affinity at 5-HT2B and DAT, resulting in 4-HO-DMiPT displaying selective activityat SERT.

The quaternary ammonium compounds were next examinedfor activityin functional assays measuring agonist potency at 5-HT1D and 5-HT2B, as well as uptake inhibition potency at DATand SERT. 4-HO-TMT, 4-AcO-TMT, 4-HO-DMPT, 4-HO-DMET, and 4-HO-DMiPTwere chosen for the functional assays based on their binding affinitiesat the four aforementioned sites of action. In fluorescence-basedagonist activity assays for 5-HT1D, four of five compounds(excluding 4-HO-DMiPT) had micromolar agonist potencies from 13.9–46.8μM (Table2 andFigure3A).

Table 2. Potency Estimations for QuaternarySalts of 4-Substituted Tryptamines at Identified Human Monoamine TransporterTargets for Uptake Inhibition Properties and for Agonist Activityat Human 5-HT Receptor Targetsa.

compoundDAT uptakeSERT uptake5-HT1D5-HT2B
 IC50 (μM)IC50 (μM)EC50 (μM)EC50 (μM)
4-HO-TMT>1006.546.82.7
4-AcO-TMT>10012.313.90.3
4-HO-DMPT83.73.332.21.3
4-HO-DMET>1007.114.73.0
4-HO-DMiPT>1003.9>10019.4
a

GBR 12909 IC50 valueat DAT = 77.3 nM. Paroxetine IC50 value at SERT = 34.9nM. 5-HT EC50 values at 5-HT1D and 5-HT2B = 515.7 and 31.0 nM, respectively.

Figure 3.

Figure 3

Functional activity of quaternary tryptammonium analogues at human5-HT1D (A) and 5-HT2B (B) receptors.

Similar low micromolar potency agonist-like functional activitywas also observed for four of five compounds at 5-HT2B,with 4-AcO-TMT exhibiting sub-micromolar potency (Table2 andFigure3B). For the 5-HT receptor functional assays,the reference ligand 5-HT had EC50 potency values of 515.7and 31.0 nM at 5-HT1D and 5-HT2B, respectively.Relative to 5-HT at these two receptor targets, all five quaternarytryptammonium compounds were weak partial agonists, as none reachedmaximal efficacy equivalent to 5-HT (Figure3).

We also examined the effects of4-HO-TMT, 4-AcO-TMT, 4-HO-DMPT,4-HO-DMET, and 4-HO-DMiPT in fluorescence-based assays assessing uptakeinhibition at DAT and SERT. Results revealed that control compoundsGBR 12909 (DAT) and paroxetine (SERT) had potencies (i.e., IC50) for inhibition of monoamine uptake of 77.3 and 34.9 nM,respectively. At DAT, the five quaternary tryptammonium compoundsdisplayed weak to no functional transporter uptake activity (84 to>100 μM;Table2). SERT uptake inhibition for all five compounds was greatly improvedversus potencies at DAT (3.3–12.3 μM;Table2), but IC50 valueswere still in the low micromolar range. Given the results for uptakeinhibition in transfected cells, we examined uptake inhibition activitiesin rat brain synaptosomes, a native tissue preparation commonly usedto study the effects of psychomotor stimulants drugs.29,30 In rat brain synaptosomes, all five compounds had >10 μMpotenciesfor uptake inhibition at DAT (Table3 andFigure4A). This is consistent with the weak potencies and affinitiesseen at these sites in the competition binding and cell-based functionalassays. For SERT uptake inhibition activities in rat brain synaptosomes,four out of five compounds displayed sub-micromolar potencies (310–840nM) with only 4-AcO-TMT displaying potency in the low micromolar range(3.5 μM;Table3 andFigure4B). Aspredicted from competition binding assays, 4-HO-DMPT, 4-HO-DMET, and4-HO-DMiPT produced the most potent uptake inhibition in rat brainsynaptosomes. All five compounds were SERT selective uptake inhibitorsrelative to other monoamine transporters, but their potencies variedconsiderably when compared to the potency of cocaine at SERT (IC50 = 263 nM). In particular, 4-HO-DMiPT displayed indistinguishablepotency for SERT uptake inhibition compared to cocaine and was themost potent compound tested in this regard. Despite these intriguingdata from cells and synaptosomes, it will be important to determinewhether these compounds are capable of entry to the central nervoussystem (CNS). The highly polar quaternary ammonium component of themolecules might preclude entry into the brain. If these compoundsare incapable of penetrating the blood brain barrier, they may representuseful peripherally restricted SERT selective molecules that can beused as pharmacological tools and templates for future research.

Table 3. Potency of Quaternary Salts of 4-SubstitutedTryptamines at Synaptosomal Rat Brain Monoamine Transportersa.

compoundDAT uptakeSERT uptake
 IC50 (μM)IC50 (μM)
4-HO-TMT>100.84
4-AcO-TMT>103.5
4-HO-DMPT>100.81
4-HO-DMET>100.59
4-HO-DMiPT>100.31
a

Cocaine IC50 values atDAT and SERT = 198 nM and 263 nM.

Figure 4.

Figure 4

Functional activity for monoamine uptake inhibition of quaternarytryptammonium analogues at DAT (A) and SERT (B) in rat brain synaptosomes.

Conclusion

The synthesis, structuralcharacterization, and pharmacologicalevaluation of eight novel quaternary tryptammonium analogues of aeruginascinhas been performed. Competitive radioligand binding assays at 46 receptorsand transporters revealed in vitro binding affinity for some of thesecompounds at four targets (5-HT1D, 5-HT2B, DAT,SERT) that could mediate pharmacological effects in vivo. The assaysalso revealed informative SARs, including a decrease in binding affinityat 5-HT1D, 5-HT2B, and DAT with the incorporationof a 4-acetoxy group and with an increase in steric bulk. For thisseries of compounds, the most substantial binding affinity and noteworthySAR was observed at SERT. Increasing the steric bulk of the quaternaryammonium unit improves affinity for SERT binding and increases potencyfor uptake inhibition, and in the case of 4-HO-DMiPT seemingly generatesa relatively potent and selective SERT ligand. Future studies shouldinvestigate potential in vivo effects of these compounds to determineif they are CNS active.

Methods

PDSP Receptor Screening,Competition Binding Assays, and FunctionalAssays

Briefly, assays were conducted using cells stablyexpressing human receptors or transporters of interest listed below:

5-HT1A, 5-HT1B, 5-HT1D, 5-ht1e, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT5A, 5-HT6, 5-HT7A, Alpha1A, Alpha1B, Alpha1D, Alpha2A, Alpha2B, Alpha2C, Beta1, Beta2, Beta3, BZP Rat Brain Site,D1, D2, D3, D4, D5, DAT, DOR, GABAA, H1, H2, H3, H4, KOR, M1, M2, M3, M4, M5, MOR, NET, PBR, SERT,Sigma 1, Sigma 2.

Cellular assays were used to determine relevanttargets at a 10μM screening concentration as well as affinity and functionalactivity for identified targets using assays described in detail athttps://pdsp.unc.edu/pdspweb/content/UNC-CH%20Protocol%20Book.pdf .

Monoamine Transporter Uptake Assays in Rat Brain

Assayswere run as described previously with little modifications.29,30 Briefly, male Sprague–Dawley rats were euthanized by CO2 narcosis, and brains were harvested to prepare synaptosomesfor uptake assays. Using the crude synaptosome fraction post-centrifugation,[3H]dopamine or [3H]5-HT was used to assesstransport activity at rDAT or rSERT, respectively.

Glossary

Abbreviations

aeruginascin or 4-PO-TMT

4-phosphoryloxy-N,N,N-trimethyltryptammonium

psilocybin or 4-PO-DMT

4-phosphoryloxy-N,N-dimethyltryptamine

psilocin or 4-HO-DMT

4-hydroxy-N,N-dimethyltryptamine

norbaeocystin or 4-PO-T

4-phosphoryloxytryptamine

baeocystinor 4-PO-NMT

4-phosphoryloxy-N-methyltryptamine

norpsilocin or 4-HO-NMT

4-hydroxy-N-methyltryptamine

4-HO-TMT

4-hydroxy-N,N,N-trimethyltryptammonium

4-AcO-TMT

4-acetoxy-N,N,N-trimethyltryptammonium

4-HO-DMPT

4-hydroxy-N,N-dimethyl-N-n-propyltryptammonium

4-HO-DMET

4-hydroxy-N,N-dimethyl-N-ethyltryptammonium

4-HO-DMiPT

4-hydroxy-N,N-dimethyl-N-isopropyltryptammonium

4-AcO-DMPT

4-acetoxy-N,N-dimethyl-N-n-propyltryptammonium

4-AcO-DMET

4-acetoxy-N,N-dimethyl-N-ethyltryptammonium

4-AcO-DMiPT

4-acetoxy-N,N-dimethyl-N-isopropyltryptammonium

5-HT1D

serotonin1D receptor

5-HT2A

serotonin 2A receptor

5-HT2B

serotonin 2B receptor

DAT

dopamine transporter

SERT

serotonin transporter

Supporting Information Available

The SupportingInformationis available free of charge athttps://pubs.acs.org/doi/10.1021/acsomega.2c03476.

  • Further details on synthesis,crystallographic datacollection and refinement, NMR data, and structural parameters (PDF)

Author Contributions

G.C.G., M.H.B.,D.R.M., and A.R.C. designed the study, analyzed the data, and contributedto writing the manuscript. D.N.K.P., J.A.G., and D.R.M. synthesizedand conducted structural characterizations of each molecule. D.W.conducted experiments with rat brain synaptosomes. All authors contributedto and approved the final version of the manuscript.

A.R.C. has anownership stake in CaaMTech, Inc., which owns patent applicationscovering new tryptamine compounds, their compositions, formulations,novel crystalline forms, methods of treatment, and methods for synthesis.This work was supported by collaborative research funds to UMass Dartmouthprovided by CaaMTech, Inc. (D.R.M.). Crystallographic and NMR datawere collected on an NSF funded instruments (CHE-1229339, CHE-1429086).This work was also supported by NIDA IRP grant number DA-000522–13and Cooperative Research and Development Agreement between NIDA andCaaMTech (M.H.B.). We acknowledge the NIMH PDSP (Contract # HHSN-271–2018–00023-C)for providingKi determinations and receptorbinding profiles. The NIMH PDSP is Directed by Bryan L. Roth MD, PhDat the University of North Carolina at Chapel Hill and Project OfficerJamie Driscoll at NIMH, Bethesda MD, USA.

The authors declare thefollowing competing financial interest(s): A.R.C. has an ownershipstake in CaaMTech, Inc., which owns patent applications covering newtryptamine compounds, their compositions, formulations, novel crystallineforms, methods of treatment, and methods for synthesis. No other authorsreport any conflicts of interest.

Supplementary Material

References

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