Proceedings of the National Academy of Sciences of the United States of America
September 8, 2026
Andrian G Basargin, Andras Domokosa, Joseph J Hennessey et al.
Of the classic psychedelics, lysergic acid diethylamide (LSD) is perhaps the best-known, but its complex chemical architecture has limited synthetic investigations aimed at generating analogues with improved safety and efficacy profiles. Here, we systematically deconstruct the tetracyclic ergoline core of LSD to create 9 simplified ergoline analogues (i.e., ergologs) and evaluate them in...
ACS Chemical Neuroscience
May 27, 2026
Grant C. Glatfelter, Serena S. Schalk, Donna Walther et al.
High Resolution Image Download MS PowerPoint Slide Tryptamine psychedelics induce psychoactive effects via agonist actions at serotonin 2A receptors (5-HT 2A ), but the compounds are generally nonselective. 4-Methoxy- N -methyl- N -isopropyltryptamine (4-MeO-MiPT) is a 5-HT 2A agonist which also blocks the 5-HT transporter (SERT) and has blunted visual and other psychedelic effects in humans....
bioRxiv : the preprint server for biology
April 21, 2026
Jeanine Yacoub, Elena Bray, Jude Bayyat et al.
Serotonergic psychedelics such as N,N-dimethyltryptamine (DMT) and 4-phosphoryloxy-N,N-dimethyltryptamine (psilocybin) show therapeutic promise for psychiatric and neurodegenerative disorders but may be limited by liabilities from serotonin (5-HT)-2A mediated psychoactive effects and potential cardiotoxicity via 5-HT2B activation. To address these limitations, we designed and synthesized...
Journal of the American Chemical Society
December 16, 2025
J.O.S. Beckett, Ryan Buzdygon, Steven Nguyen et al.
1 citation
A light-induced cyclization via a radical spin-center shift process that results in the direct functionalization of the indole ring at the C4-position is developed into a practical method for the synthesis of medicinally active, ring-constrained tryptamine analogs. Amino acids were coupled to tryptamine and irradiated with UV light to produce a library of lactams bridging the C3- and...
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...
ACS Pharmacology & Translational Science
August 22, 2025
Devin P. Effinger, Serena S. Schalk, Jillian L. King et al.
3 citations
High Resolution Image Download MS PowerPoint Slide Microdosing, the prolonged ingestion of psychedelics at subhallucinogenic doses, has gained popularity for its perceived cognitive and emotional benefits. Psychedelics have high affinity for 5-HT 2B receptors, a receptor known to cause human heart disease with strong chronic activation. We investigated the effects of microdosed psychedelics on...