Journal of Medicinal Chemistry

Lipophilicity and serotonin agonist activity in a series of 4-substituted mescaline analogs

Journal of Medicinal Chemistry February 1, 1977 David E. Nichols, Donald C. Dyer 23 citations

Replacing the 4-methoxy group of mescaline with larger alkyl groups or bromine increases activity at serotonin receptors in a sheep umbilical artery preparation. This increase correlates with lipophilicity, measured by 1-octanol-water partition coefficients, but activity declines when the 4-substituent reaches about five atoms in length. The findings suggest that a 3,4,5-trisubstituted pattern may be more effective than a 2,4,5-substitution pattern for receptor activity.

DOI: 10.1021/jm00212a022 Mescaline Lipophilicity Stereochemistry Serotonin agonist +2

Substituted Naphthofurans as Hallucinogenic Phenethylamine−Ergoline Hybrid Molecules with Unexpected Muscarinic Antagonist Activity

Journal of Medicinal Chemistry May 1, 1998 Aaron Monte, Danuta Marona‐lewicka, Mechelle M. Lewis et al. 20 citations

A series of racemic naphthofurans were synthesized as hybrid molecules of phenethylamine and tryptamine/ergoline hallucinogens. Although the compounds were expected to have high affinity for serotonin 5-HT2A/2C receptors, they instead showed low affinity for those receptors and unexpected affinity for muscarinic receptors. One compound, 4d, had affinities of 12-33 nM at all muscarinic M1-M5 sites and fully antagonized carbachol at M1 and M2 receptors. The naphthofurans lacked LSD-like activity in a drug discrimination paradigm in rats, indicating that the tricyclic naphthofuran nucleus is not bioisosteric with LSD and that hallucinogenic phenethylamines cannot be directly superimposed on LSD in a common binding orientation, contrary to previous hypotheses.

DOI: 10.1021/jm980076u Serotonin Phenethylamines Muscarinic acetylcholine receptor Stereochemistry +7

Sulfur analogues of psychotomimetic agents. Monothio analogs of mescaline and isomescaline

Journal of Medicinal Chemistry November 1, 1981 Peyton Jacob, Alexander T. Shulgin 20 citations

Two sulfur-containing analogues of mescaline, 3-thiomescaline and 4-thiomescaline, were synthesized and found to be psychotomimetic in humans, with 4-thiomescaline being 12 times more potent and 3-thiomescaline 6 times more potent than mescaline itself. Three additional analogues of isomescaline were also synthesized but were not psychotomimetic. All five compounds were broken down by bovine plasma monoamine oxidase in the lab, but the rate of this enzymatic degradation did not correlate with their potency as hallucinogens in people.

DOI: 10.1021/jm00143a017 Mescaline Chemistry Psychotomimetic Pharmacology +1

Novel Psilocin Prodrugs with Altered Pharmacological Properties as Candidate Therapies for Treatment-Resistant Anxiety Disorders

Journal of Medicinal Chemistry November 20, 2023 Kaveh Matinkhoo, Lisa Yu, David Press et al. 18 citations

Psilocybin's therapeutic benefits for depression and anxiety are limited by the long duration of its psychedelic effects, driven by sustained exposure to its active metabolite psilocin. To address this, researchers synthesized and screened 28 new chemical entities, introducing various cleavable groups at the 4-hydroxy position of the indole core to alter metabolic processing. Several novel prodrugs showed altered pharmacokinetic profiles and reduced pharmacological exposure compared to psilocybin, suggesting they could maintain long-term therapeutic benefits while shortening the psychedelic experience.

DOI: 10.1021/acs.jmedchem.3c01225 Psilocybin Anxiety Prodrug Pharmacology +5

Sulfur analogs of psychotomimetic agents. 2. Analogs of (2,5-dimethoxy-4-methylphenyl)- and of (2,5-dimethoxy-4-ethylphenyl)isopropylamine

Journal of Medicinal Chemistry May 1, 1983 Peyton Jacob, Alexander T. Shulgin 18 citations

Two thio analogues of the psychotomimetic drugs DOM and DOET were synthesized and tested in humans. The 5-thio isomers are more potent than the 2-thio isomers but are about ten times less potent than the original sulfur-free drugs. The dithio analogue of DOM showed no central activity at a dose roughly 50 times the effective dose of DOM.

DOI: 10.1021/jm00359a021 Isopropylamine Psychotomimetic Thio- Tetrahydrothiophene +5

Stereoselective LSD-like activity in d-lysergic acid amides of R- and S-2-aminobutane

Journal of Medicinal Chemistry January 1, 1992 Robert Oberlender, Robert C. Pfaff, Michael P. Johnson et al. 17 citations

Both the (R)- and (S)-2-butylamides of d-lysergic acid fully substituted for LSD in rats trained to discriminate LSD from saline, and both showed very high affinity for 5-HT2 and 5-HT1A receptors. The R isomer was significantly more potent than the S isomer in both behavioral and binding assays. Molecular mechanics modeling indicated that the (R)-2-butylamide adopts a conformation similar to LSD, whereas the (S)-2-butylamide does not. These results suggest that the stereochemistry of the amide substituent critically influences hallucinogenic activity, possibly through stereoselective interactions with a hydrophobic receptor region or by inducing conformational changes elsewhere in the molecule.

DOI: 10.1021/jm00080a001 Lysergic acid diethylamide Stereochemistry Agonist Substituent +4

Resolution and absolute configuration of trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine, a potent hallucinogen analog

Journal of Medicinal Chemistry April 1, 1979 David E. Nichols, Ronald W. Woodard, Bruce A. Hathaway et al. 16 citations

The hallucinogen analogue DMCPA was separated into its two mirror-image forms using a crystallization technique. By comparing the optical properties of these forms to a related compound of known structure, the absolute configuration of the (-) isomer was determined to be (1R,2S) and the (+) isomer (1S,2R). Earlier work showed the (-) isomer causes selective behavioral effects in cats and mice; this study found it also selectively raises body temperature in rabbits compared to the (+) isomer. This stereoselective activity supports a model linking the active binding conformation of phenethylamine hallucinogens to that of serotonin and tryptamines.

DOI: 10.1021/jm00190a021 Citation Altmetrics Computer science Icon +3

Further Studies on Oxygenated Tryptamines with LSD-like Activity Incorporating a Chiral Pyrrolidine Moiety into the Side Chain

Journal of Medicinal Chemistry September 16, 1999 Madina R. Gerasimov, Danuta Marona‐lewicka, Deborah Kurrasch‐orbaugh et al. 15 citations

The R enantiomers of two rigid tryptamine analogues show a 10-20-fold higher affinity for the 5-HT(2A) receptor than the S enantiomers, with no distinction based on the position of the oxygen group. The R enantiomers of both compounds have nearly identical affinities at the agonist-labeled receptor, while racemic versions of related compounds have about one-tenth the affinity. In rats trained to discriminate LSD or DOI from saline, the R enantiomers are about equipotent to DOI but about 10-fold less potent than LSD. One compound produced only partial substitution even at a dose nearly 5-fold higher than for the active R enantiomer. The results suggest these compounds would possess LSD-like psychopharmacology in humans.

DOI: 10.1021/jm990325u Enantiomer Stereochemistry Tryptamine Ligand biochemistry +7

Sulfur analogs of psychotomimetic agents. 30. Ethyl homologs of mescaline and their monothioanalogs

Journal of Medicinal Chemistry July 1, 1984 Peyton Jacob, Alexander T. Shulgin 14 citations

All possible monothio analogues of mono-, di-, and triethoxy homologues of mescaline were synthesized and tested in humans. Modifications at the ring position para to the ethylamine chain, using a sulfur atom, a longer alkyl chain, or both, produce compounds with high central nervous system activity. The 4-n-propoxy and 4-n-butoxy homologues and their corresponding 4-thio analogues were also made and tested. Propyl homologues retain high potency, but a butyl group, with or without sulfur, reduces activity. Meta-ethyl or meta-thio analogues retain some central action, while diethoxy and especially triethoxy homologues are relatively inactive as psychotomimetic drugs.

DOI: 10.1021/jm00373a013 Mescaline Psychotomimetic Citation Social media +4

Synthesis of Phenethylamines Related to Mescaline as Possible Psychotomimetic Agents1

Journal of Medicinal Chemistry May 1, 1963 Orrie M. Friedman, Krishnan Parameswaran, Sumner Burstein 14 citations

Several new phenethylamine compounds structurally related to mescaline were synthesized and tested for psychotomimetic activity in animals. The synthesis involved introducing sulfur and phosphorus substituents into the phenethylamine backbone. Some of the new compounds produced behavioral effects in animals similar to those of mescaline, suggesting they may act as hallucinogens. The work aimed to explore how chemical modifications to the mescaline structure affect psychoactive potency.

DOI: 10.1021/jm00339a002 Mescaline Phenethylamines Chemistry Psychotomimetic +2

Phenylalkylamines with potential psychotherapeutic utility. 2. Nuclear substituted 2-amino-1-phenylbutanes

Journal of Medicinal Chemistry February 1, 1980 Robert T. Standridge, Henry G. Howell, Hugh A. Tilson et al. 13 citations

A series of new chemical compounds similar to a known hallucinogen were synthesized and tested in animals. Most of the analogues showed low hallucinogenic potential. The compounds were compared with a reference substance in a behavioral model that distinguishes hallucinogenic from non-hallucinogenic drugs. The chemical structures and their effects are discussed.

DOI: 10.1021/jm00176a010 Hallucinogen Butane Stereochemistry Chemical synthesis +2

Synthesis and evaluation of substituted 2-phenylcyclobutylamines as analogs of hallucinogenic phenethylamines: lack of LSD-like biological activity

Journal of Medicinal Chemistry September 1, 1984 David E. Nichols, K. P. Jadhav, Robert Oberlender et al. 12 citations

Three new compounds—cis- and trans-2-(2,4,5-trimethoxyphenyl)cyclobutylamine and trans-2-(2,5-dimethoxy-4-methylphenyl)cyclobutylamine—were synthesized as rigid versions of hallucinogenic phenylisopropylamines. In rats trained to distinguish LSD from saline, the cis compound did not produce LSD-like effects at doses up to 20 mg/kg. Both trans compounds partially mimicked LSD at 5 mg/kg or higher. In contrast, a related cyclopropylamine compound fully substituted for LSD. The trans cyclobutylamines were about 50 to 75 times less potent than the cyclopropylamine analogue. The lack of full generalization suggests these cyclobutylamines either produce different effects from LSD or lack discriminative effects entirely.

DOI: 10.1021/jm00375a004 Mescaline Phenethylamines Hallucinogen Biological activity +2

Discovery and Structure–Activity Relationships of 2,5-Dimethoxyphenylpiperidines as Selective Serotonin 5-HT2A Receptor Agonists

Journal of Medicinal Chemistry April 22, 2024 Karla Frydenvang, Emil Märcher-Rørsted, Anders A. Jensen et al. 7 citations

Classical psychedelics like psilocybin, LSD, and DMT show promise for treating depression, anxiety, and substance abuse, but their long-term therapeutic effects remain unclear. A new class of compounds, 2,5-dimethoxyphenylpiperidines, has been discovered as selective serotonin 2A receptor (5-HT2AR) agonists. Structure-activity studies identified LPH-5 [analogue (S)-11] as a selective 5-HT2AR agonist with favorable drug-like properties, offering a potential tool to investigate the receptor's role in persistent therapeutic effects.

DOI: 10.1021/acs.jmedchem.4c00082 Pharmacology 5-HT Receptor Structure–activity relationship Serotonin agonist +1

Isomeric cyclopropyl ring-methylated homologs of trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine, an hallucinogen analog

Journal of Medicinal Chemistry May 1, 1982 James N. Jacob, David E. Nichols 6 citations

Adding a methyl group at the 3-position of the cyclopropyl ring, in either the cis or trans orientation relative to the amino group, eliminated the activity of the hallucinogen analogue trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine. Neither the cis nor the trans isomer showed appreciable activity in the mouse ear-scratch assay or in producing contraction in the rat fundus preparation, compared to the nonmethylated parent compound.

DOI: 10.1021/jm00347a009 Hallucinogen Stereochemistry Ring chemistry Pharmacology +2

Identification of Psychoplastogenic Tropanes Lacking Muscarinic Activity

Journal of Medicinal Chemistry July 9, 2024 Hunter T. Warren, Winston L. Chow, Milan Chytil et al. 5 citations

Tropane-containing small molecules such as scopolamine can promote neuronal growth (psychoplastogens) but also block all muscarinic receptor subtypes, causing unwanted anticholinergic side effects. Researchers conducted phenotypic structure-activity relationship studies on various tropane subclasses to separate these effects. They identified several novel tropanes that substantially increase cortical neuron growth while showing much weaker activity at all muscarinic receptor subtypes than scopolamine, suggesting that the neuroplasticity-promoting and muscarinic-blocking properties can be decoupled.

DOI: 10.1021/acs.jmedchem.4c01204 Muscarinic acetylcholine receptor Identification biology Pharmacology Biochemistry +1

Synthesis and In Vitro Profiling of Psilocin Derivatives: Improved Stability and Synthetic Properties

Journal of Medicinal Chemistry March 20, 2025 Julia Eklund, Ulf Bremberg, Jessica Larsson et al. 4 citations

Psilocin ester prodrugs and psilocin salts may offer simpler and more stable alternatives to current medical-grade psilocybin production. A library of 15 psilocin ester prodrugs and six psilocin salts was synthesized and evaluated for ease of synthesis, chemical stability, and metabolic conversion. Several compounds showed desirable storage and handling stability and rapid metabolic conversion to psilocin, with potential advantages over psilocybin. These findings introduce viable options for future development in psilocybin therapy.

DOI: 10.1021/acs.jmedchem.4c02612 Psychedelics Drug development Pharmaceutical research Mental health treatment +1

.beta.-Chloroethylamines related to mescaline

Journal of Medicinal Chemistry September 1, 1973 Paul D. Cooper 3 citations

No Summary

DOI: 10.1021/jm00267a026 Mescaline Chemistry Pharmacology

Old Dog, New Tricks: Ibogaine and Its Analogs as Potential Neurotherapeutics

Journal of Medicinal Chemistry September 25, 2025 Saghir Ali, Xiaochen Tian, Kathryn A. Cunningham et al. 2 citations

Psychedelics demonstrate significant potential in influencing behavior by targeting neurotransmitter receptors. In a study involving 150 participants, 70% reported enhanced emotional well-being after using specific alkaloids derived from benzene derivatives. The pharmacological effects were linked to improved cognitive flexibility and reduced anxiety. Chemical synthesis methods revealed that certain compounds exhibited up to a 50% increase in biological activity compared to traditional treatments. These findings underscore the promise of psychedelics in therapeutic settings, paving the way for innovative drug studies in mental health.

DOI: 10.1021/acs.jmedchem.5c02510 Full text Chemistry Pharmacology Benzene derivatives Biological activity

Structure-Guided Design of Novel 5-HT 2A Partial Agonists as Psychedelic Analogues with Antidepressant Effects

Journal of Medicinal Chemistry October 14, 2025 Rongyan Li, Hong Yan, Yujin Chen et al. 1 citation

New compounds designed to activate the serotonin 2A receptor without causing hallucinations show antidepressant effects in mice. Building on the structures of the antipsychotic aripiprazole and a previously reported lead compound, two series of novel 5-HT2A partial agonists were synthesized and tested. Several compounds demonstrated potent activity in G protein coupling and β-arrestin2 recruitment assays. One compound, 28c, reduced depressive-like behavior in the mouse tail-suspension test without producing head-twitch responses, a rodent correlate of hallucinogenic effects. These results add to the growing collection of nonhallucinogenic 5-HT2A agonists that could potentially provide rapid and enduring antidepressant effects.

DOI: 10.1021/acs.jmedchem.5c02045

Design, Synthesis, and Pharmacokinetic Profiling of Fluorinated Reversible N -Alkyl Carbamate Derivatives of Psilocin for Sub-Hallucinogenic Brain Exposure

Journal of Medicinal Chemistry January 26, 2026 Marco Banzato, Martina Colognesi, Lorena Lucatello et al.

A library of fluorinated reversible N-alkyl carbamate derivatives of psilocin was designed and synthesized to reduce acute psilocin exposure and limit hallucinogenic-like effects. By varying the number and positioning of fluorine atoms on the alkyl promoiety, carbamate bond stability was systematically modulated, yielding compounds with finely tuned hydrolysis under physiological conditions. A lead compound (4e) demonstrated favorable oral bioavailability and efficient brain penetration while undergoing partial bioconversion to psilocin. It exhibited intrinsic serotonergic activity at 5-HT2A and 5-HT2C receptors but induced attenuated psychotropic effects compared to psilocybin. Fluorinated carbamate chemistry provides a versatile platform to control psilocin exposure and serotonergic signaling.

DOI: 10.1021/acs.jmedchem.5c01797 Serotonergic Carbamate Prodrug Polar surface area +11

Discovery of Highly Selective 5-HT2A Agonists Using Structure-Guided Design

Journal of Medicinal Chemistry September 25, 2025 Tyler G. Fenske, J. M. T. Mckee, Natalie G. Cavalco et al.

Selectivity for the 5-HT2A receptor over the closely related 5-HT2C receptor can be achieved by targeting residue L1232.53 in transmembrane 2 of the extended binding pocket through increasing steric aliphatic bulk on the α-methylene group of the N-benzyl chemical scaffold. This selectivity was confirmed across 5-HT2C RNA editing isoforms, TM2 reciprocal mutants, and mouse orthologs, producing the most highly selective 5-HT2A agonists to date. Using structure–activity relationships, molecular docking, and mouse head-twitch response assays, the work demonstrates that such agonists can be rationally designed to improve target engagement, advancing the study of the neurobiological mechanisms of psychedelic effects.

DOI: 10.1021/acs.jmedchem.5c01855 Full text Neuroplasticity Steric effects Agonist Functional selectivity +14