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.
Journal of Medicinal Chemistry
September 1, 1973
Paul D. Cooper
3 citations
No Summary
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.
Journal of Medicinal Chemistry
June 18, 2025
Alexandra Sink, Eline Pottie, Samuel J Carter et al.
2 citations
A photoswitchable ligand for the serotonin 2A receptor (5-HT2AR) was designed to independently study G protein- and β-arrestin2-dependent signaling pathways. The cis-photoisomer binds the receptor with greater affinity than the trans-isomer, at nanomolar concentrations. In functional assays, this ligand showed a preference for recruiting β-arrestin2 over mini-Gαq relative to LSD, offering a tool to investigate β-arrestin2's role in 5-HT2AR signaling and its potential involvement in psychedelic effects.
Journal of Medicinal Chemistry
January 23, 2025
Allana Cristina Faustino Martins, Bretton Badenoch, Roberto da Silva Gomes
2 citations
Ketamine provides rapid relief for treatment-resistant depression. As an NMDAR antagonist, it may affect prefrontal cortex neurons. The (R)-enantiomer is the most effective and least abuseable antidepressant, though only the (S)-enantiomer is FDA-approved. The metabolite (2R,6R)-Hydroxynorketamine inhibits mGlu2 in presynaptic glutamatergic neurons, increasing BDNF release, which activates TrkB and promotes synaptogenesis. This Perspective explores ketamine's synthesis, pharmacology, metabolism, and effects in animal and human studies to explain differences in biological activity between its enantiomers.
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.
Journal of Medicinal Chemistry
July 29, 2025
Xu Cheng, Fan Jiang, Lixin Liu et al.
1 citation
A new compound, B11, shows promise as a rapid-acting antidepressant in preclinical models. Unlike existing fast-acting treatments such as esketamine and psychedelics, which carry risks of psychotic side effects and substance abuse, B11 activates the TrkB-CREB signaling axis without interfering with targets linked to those side effects. B11 readily crosses the blood-brain barrier and has a favorable pharmacokinetic profile allowing oral administration. These findings highlight the potential for optimized fast-onset antidepressants to address unmet needs in treating major depressive disorder and underscore the role of neuroplasticity modulation in drug discovery.
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.
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.