Journal of Medicinal Chemistry - The Consciousness Library

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.

Psilocybin, the phosphorylated prodrug of psilocin, holds therapeutic promise across a range of neuropsychiatric conditions, yet its clinical utility is constrained by acute psychoactive effects. Here, we report the rational design, synthesis, and evaluation of a focused library of fluorinated reversible N-alkyl carbamate derivatives of psilocin aimed at reducing acute psilocin exposure and...

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

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

Depression is primarily treated with selective serotonin reuptake inhibitors (SSRIs), which are limited by delayed onset of effects and low rates of remission. Recent studies showed that serotonergic psychedelics such as psilocybin can reduce depressive symptoms both rapidly and enduringly. Such effects have been associated with the activation of the serotonin 2A (5-HT2A) receptor in the...

DOI: 10.1021/acs.jmedchem.5c02045

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.

With a resurgence in interest in psychedelics as rapid-acting and durable neuroplastic therapies, there is a critical need to develop more selective 5-HT 2A agonists to investigate the basic neurobiological mechanisms of psychedelics. Here, we show that selectivity for 5-HT 2A over the closely related 5-HT 2C receptor can be leveraged using structure-based design to target residue L123 2.53 in...

DOI: 10.1021/acs.jmedchem.5c01855 Full text Neuroplasticity Steric effects Agonist Functional selectivity +13

Discovery of Rapid-Acting, Orally Available Antidepressants by Activating TrkB Signaling.

Journal of Medicinal Chemistry July 29, 2025 Xu Cheng, Fan Jiang, Lixin Liu et al. 1 citation

Major depressive disorder (MDD) remains a significant global health burden, and its current treatments are limited by the delayed onset of efficacy weeks after dosing. While esketamine and psychedelics were clinically successful as rapid-acting antidepressants in recent years, these molecules are heavily associated with psychotic side effects and the risks of substance abuse. In this study, we...

DOI: 10.1021/acs.jmedchem.5c01750 Full text Neuroplasticity Depression treatment Mental health therapy Mood disorder treatment +16

Design, Synthesis, and In Vitro Characterization of a Tryptamine-Based Visible-Light Photoswitchable 5-HT2AR Ligand Showing Efficacy Preference for β-Arrestin over Mini-Gq.

Journal of Medicinal Chemistry June 18, 2025 Alexandra Sink, Eline Pottie, Samuel J Carter et al. 2 citations

The serotonin 2A receptor (5-HT2AR) modulates various neurotransmitter systems and is implicated in psychiatric disorders, including depression and schizophrenia. Despite progress, the detailed mechanisms of signaling at the 5-HT2AR and its therapeutic implications remain unclear, warranting further exploration. Overcoming the limitations of conventional pharmacology, photopharmacology...

DOI: 10.1021/acs.jmedchem.5c00442 Full text 5-ht2a receptor Depression Optogenetics Photopharmacology +8

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

As interest in using psilocybin therapy for treating mental health disorders intensifies, the need for efficient production methods becomes increasingly important. Current medical-grade psilocybin production is inefficient and relies on a complicated multistep synthesis. This study has explored and evaluated psilocin ester prodrugs and psilocin salts as potential alternatives to psilocybin,...

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

Insights for the Next Generation of Ketamine for the Treatment of Depressive Disorder.

Journal of Medicinal Chemistry January 23, 2025 Allana Cristina Faustino Martins, Bretton Badenoch, Roberto da Silva Gomes 2 citations

Treatment-resistant depression responds quickly to ketamine. As an N-methyl-d-aspartate receptor (NMDAR) antagonist, ketamine may affect prefrontal cortex (PFC) neurons. Recent investigations reveal that the (R)-enantiomer is the most effective and least abuseable antidepressant. The Food and Drug Administration approves only the (S)-enantiomer for medical usage. (2R,6R)-Hydroxynorketamine...

DOI: 10.1021/acs.jmedchem.4c02467 Full text Depression treatment Ketamine therapy Mental health research Antidepressant medication

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 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...

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

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 such as psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT) are showing promising results in clinical trials for a range of psychiatric indications, including depression, anxiety, and substance abuse disorder. These compounds are characterized by broad pharmacological activity profiles, and while the acute mind-altering effects can be ascribed...

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

Structural Basis for Molecular Recognition of Cannabinoids by Inhibitory Cys-Loop Channels.

Journal of Medicinal Chemistry March 14, 2024 Lautaro D Alvarez, N R Carina Alves 7 citations

Cannabis sativa has a long history of medicinal use, dating back to ancient times. This plant produces cannabinoids, which are now known to interact with several human proteins, including Cys-loop receptors for glycine (GlyR) and gamma-aminobutyric acid (GABAAR). As these channels are the primary mediators of inhibitory signals, they contribute to the diverse effects of cannabinoids on the...

DOI: 10.1021/acs.jmedchem.3c02391 Full text

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

The psychedelic prodrug psilocybin has shown therapeutic benefits for the treatment of numerous psychiatric conditions. Despite positive clinical end points targeting depression and anxiety, concerns regarding the duration of the psychedelic experience produced by psilocybin, associated with enduring systemic exposure to the active metabolite psilocin, pose a barrier to its therapeutic...

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

What We Have Gained from Ibogaine: α3β4 Nicotinic Acetylcholine Receptor Inhibitors as Treatments for Substance Use Disorders.

Journal of Medicinal Chemistry January 12, 2023 Carolyn J Straub, Lisa E Rusali, Kyle M Kremiller et al. 19 citations

For decades, ibogaine─the main psychoactive alkaloid found in Tabernanthe iboga─has been investigated as a possible treatment for substance use disorders (SUDs) due to its purported ability to interrupt the addictive properties of multiple drugs of abuse. Of the numerous pharmacological actions of ibogaine and its derivatives, the inhibition of α3β4 nicotinic acetylcholine receptors (nAChRs),...

DOI: 10.1021/acs.jmedchem.2c01562 Full text Ibogaine: natural compound Plant medicine Drug addiction Suds +5

Discovery of β-Arrestin-Biased 25CN-NBOH-Derived 5-HT2A Receptor Agonists.

Journal of Medicinal Chemistry September 22, 2022 Christian B M Poulie, Eline Pottie, Icaro A Simon et al. 32 citations

The serotonin 2A receptor (5-HT2AR) is the mediator of the psychedelic effects of serotonergic psychedelics, which have shown promising results in clinical studies for several neuropsychiatric indications. The 5-HT2AR is able to signal through the Gαq and β-arrestin effector proteins, but it is currently not known how the different signaling pathways contribute to the therapeutic effects...

DOI: 10.1021/acs.jmedchem.2c00702 Full text Psychedelic-medicine Pharmacology Mental-health Serotonin-research

Synthesis and κ-opioid receptor activity of furan-substituted salvinorin A analogues.

Journal of Medicinal Chemistry December 26, 2014 Andrew P Riley, Chad E Groer, David Young et al. 115 citations

The neoclerodane diterpene salvinorin A, found in the leaves of Salvia divinorum, is a potent κ-opioid receptor agonist, making it an attractive scaffold for development into a treatment for substance abuse. Although several successful semisynthetic studies have been performed to elucidate structure-activity relationships, the lack of analogues with substitutions to the furan ring of salvinorin...

DOI: 10.1021/jm501521d Full text

Neoclerodanes as atypical opioid receptor ligands.

Journal of Medicinal Chemistry May 9, 2013 Thomas E Prisinzano 22 citations

The neoclerodane diterpene salvinorin A is the major active component of the hallucinogenic mint plant Salvia divinorum Epling and Játiva (Lamiaceae). Since the finding that salvinorin A exerts its potent psychotropic actions through the activation of opioid receptors, the site of action of morphine and related analogues, there has been much interest in elucidating the underlying mechanisms...

DOI: 10.1021/jm400388u Full text Dependence Receptors Morphine Targeting +11

1-[(1-Methyl-1H-imidazol-2-yl)methyl]-4-phenylpiperidines as mGluR2 Positive Allosteric Modulators for the Treatment of Psychosis

Journal of Medicinal Chemistry March 2, 2011 Lei Zhang, Michael A. Brodney, John Candler et al. 32 citations

A novel series of mGluR2 positive allosteric modulators (PAMs), 1-[(1-methyl-1H-imidazol-2-yl)methyl]-4-phenylpiperidines, is herein disclosed. Structure-activity relationship studies led to potent, selective mGluR2 PAMs with excellent pharmacokinetic profiles. A representative lead compound (+)-17e demonstrated dose-dependent inhibition of methamphetamine-induced hyperactivity and...

DOI: 10.1021/jm101414h Mescaline Allosteric regulation Methamphetamine Pharmacology +3

1-Aminomethylbenzocycloalkanes: conformationally restricted hallucinogenic phenethylamine analogues as functionally selective 5-HT2A receptor agonists.

Journal of Medicinal Chemistry September 21, 2006 Thomas H. Mclean, Jason C. Parrish, Michael R Braden et al. 115 citations

A series of conformationally restricted analogues of the hallucinogenic phenethylamine 1 (2,5-dimethoxy-4-bromophenethylamine, 2C-B) was synthesized to test several hypotheses concerning the bioactive conformation of phenethylamine ligands upon binding to the 5-HT(2A) receptor. These benzocycloalkane analogues were assayed for their receptor binding affinity and ability to activate downstream...

DOI: 10.1021/jm060656o Full text LSD Psychopharmacology: neuropharmacology Drug action Brain chemistry +15

C-(4,5,6-Trimethoxyindan-1-yl)methanamine: A Mescaline Analogue Designed Using a Homology Model of the 5-HT2AReceptor

Journal of Medicinal Chemistry June 21, 2006 Thomas H. Mclean, James J. Chambers, Jason C. Parrish et al. 24 citations

A conformationally restricted analogue of mescaline, C-(4,5,6-trimethoxyindan-1-yl)-methanamine, was designed using a 5-HT(2A) receptor homology model. The compound possessed 3-fold higher affinity and potency than and efficacy equal to that of mescaline at the 5-HT(2A) receptor. The new analogue substituted fully for LSD in drug discrimination studies and was 5-fold more potent than mescaline....

DOI: 10.1021/jm060272y Mescaline Potency Stereochemistry Homology modeling +8

Synthesis and Pharmacological Characterization of a Series of Geometrically Constrained 5-HT2A/2C Receptor Ligands

Journal of Medicinal Chemistry July 1, 2003 James J. Chambers, Jason C. Parrish, Niels Jensen et al. 27 citations

In studies of the SAR of phenethylamine-type serotonin 5-HT(2A) receptor agonists, substituted conformationally constrained tetrahydronaphthofurans were designed to investigate the optimal conformation of the 2-aminoethyl moiety. These compounds were tested using in vitro assays for affinity at 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptors. The benzofuran-containing analogues, 6a and 6b, had...

DOI: 10.1021/jm030064v Serotonin Stereochemistry Phenethylamine Intrinsic activity +6

Lysergamides of Isomeric 2,4-Dimethylazetidines Map the Binding Orientation of the Diethylamide Moiety in the Potent Hallucinogenic Agent N,N-Diethyllysergamide (LSD)

Journal of Medicinal Chemistry September 1, 2002 David E. Nichols, Stewart Frescas, Danuta Marona‐lewicka et al. 89 citations

Lysergic acid amides were prepared from (R,R)-(-)-, (S,S)-(+)-, and cis-2,4-dimethyl azetidine. The dimethylazetidine moiety is considered here to be a rigid analogue of diethylamine, and thus, the target compounds are all conformationally constrained analogues of the potent hallucinogenic agent, N,N-diethyllysergamide, LSD-25. Pharmacological evaluation showed that...

DOI: 10.1021/jm020153s Lysergic acid diethylamide Hallucinogen Moiety Stereochemistry +5

Enantiospecific Synthesis and Pharmacological Evaluation of a Series of Super-Potent, Conformationally Restricted 5-HT2A/2C Receptor Agonists

Journal of Medicinal Chemistry January 26, 2001 James J. Chambers, Deborah Kurrasch‐orbaugh, Matthew Parker et al. 98 citations

The affinity of ligands for either the 5-HT(2A) or 5-HT(2C) agonist binding site was enhanced by modification of the 2,5-oxygen substituents that are found in typical hallucinogenic amphetamines such as 4b (DOB). Restriction of the conformationally flexible 2,5-dimethoxy substituents into fused dihydrofuran rings generally resulted in increased potency relative to the parent 2,5-dimethoxy...

DOI: 10.1021/jm000491y Enantiomer Stereochemistry Potency Stereoselectivity +8

Effect of Ring Fluorination on the Pharmacology of Hallucinogenic Tryptamines

Journal of Medicinal Chemistry October 19, 2000 Joseph B. Blair, Deborah Kurrasch‐orbaugh, Danuta Marona‐lewicka et al. 132 citations

A series of fluorinated analogues of the hallucinogenic tryptamines N,N-diethyltryptamine (DET), 4-hydroxy-N,N-dimethyltryptamine (4-OH-DMT, psilocin), and 5-methoxy-DMT was synthesized to investigate possible explanations for the inactivity of 6-fluoro-DET as a hallucinogen and to determine the effects of fluorination on the molecular recognition and activation of these compounds at serotonin...

DOI: 10.1021/jm000339w Serotonin Tryptamines Hallucinogen Partial agonist +5

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 enantiomers of 3-(N-methylpyrrolidin-2-ylmethyl)-5-methoxyindole, 1, and 3-(N-methylpyrrolidin-2-ylmethyl)-4-hydoxyindole, 3, were prepared using an asymmetric synthesis that employed (+)- or (-)-proline. A new approach was developed that had certain advantages over the synthesis originally reported for the isomers of 1. (+/-)-3-(N-Methylpyrrolidin-3-yl)-4-hydroxyindole, 5, was also...

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

Thieno[3,2-b]- and Thieno[2,3-b]pyrrole Bioisosteric Analogues of the Hallucinogen and Serotonin Agonist N,N-Dimethyltryptamine

Journal of Medicinal Chemistry March 1, 1999 Joseph B. Blair, Danuta Marona‐lewicka, Arthi Kanthasamy et al. 63 citations

The synthesis and biological activity of 6-[2-(N, N-dimethylamino)ethyl]-4H-thieno[3,2-b]pyrrole (3a) and 4-[2-(N, N-dimethylamino)ethyl]-6H-thieno[2,3-b]pyrrole (3b), thienopyrroles as potential bioisosteres of N,N-dimethyltryptamine (1a), are reported. Hallucinogen-like activity was evaluated in the two-lever drug discrimination paradigm using LSD- and DOI-trained rats. Neither 3a nor 3b...

DOI: 10.1021/jm980692q Serotonin Tryptamines Hallucinogen Bioisostere +11

A Novel (Benzodifuranyl)aminoalkane with Extremely Potent Activity at the 5-HT2A Receptor

Journal of Medicinal Chemistry December 1, 1998 Matthew Parker, Danuta Marona‐lewicka, Virginia L. Lucaites et al. 69 citations

ADVERTISEMENT RETURN TO ISSUEPREVLetterNEXTA Novel (Benzodifuranyl)aminoalkane with Extremely Potent Activity at the 5-HT2A Receptor 1Matthew A. Parker, Danuta Marona-Lewicka, Virginia L. Lucaites, David L. Nelson, and David E. NicholsView Author Information Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West...

DOI: 10.1021/jm9803525 Citation Library science Pharmacy World wide web +1

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