Discovery of Highly Selective 5-HT2A Agonists Using Structure-Guided Design
Tyler G. Fenske, J. M. T. Mckee, Natalie G. Cavalco, Serena S. Schalk, Emma M. Bonniwell, Josie C. Lammers, Naomi Shacham, Bruna Cuccurazzu, Adam L. Halberstadt, John D. Mccorvy
Journal of Medicinal Chemistry September 25, 2025 DOI: 10.1021/acs.jmedchem.5c01855 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Topics | Neuroplasticity Serotonin |
| Keywords | Steric effects Agonist Functional selectivity Receptor Transmembrane protein Binding selectivity Binding site Combinatorial chemistry Computational biology Structure–activity relationship Drug discovery Molecular recognition Pharmacology Chemical synthesis Transmembrane domain Benzene derivatives |
| Key findings | Selectivity for 5-HT2A over 5-HT2C can be achieved by targeting residue L1232.53 in TM2 with increased steric aliphatic bulk on the α-methylene group of the N-benzyl scaffold. |
Abstract
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 transmembrane 2 (TM2) of the extended binding pocket by increasing steric aliphatic bulk on the α-methylene group of the N -benzyl chemical scaffold. Furthermore, we comprehensively confirm selectivity at 5-HT 2C RNA editing isoforms, TM2 reciprocal 5-HT 2A and 5-HT 2C mutants, and mouse 5-HT 2A and 5-HT 2C orthologs, to form a complete profile for highly selective 5-HT 2A agonists to date. Using a combination of structure–activity relationships, molecular docking, and mouse head-twitch response assays, we show that 5-HT 2A -selective agonists can be rationally designed to improve 5-HT 2A target engagement, further advancing the study into the neurobiological mechanisms of psychedelic effects.
Comparable studies
Other experimental studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Healthy human volunteers | 1998 | Experimental study | |
| Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin | 2000 | Experimental study | |
| Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity Rat brain | 1988 | Experimental study | |
| The molecular mechanism of "ecstasy" [3,4-methylenedioxy-methamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Human platelet plasma membrane vesicles and bovine adrenal chromaffin granule membrane... | 1992 | Laboratory study | |
| 5-HT2AReceptor-Mediated Regulation of Brain-Derived Neurotrophic Factor mRNA in the Hippocampus and the Neocortex Rat brain | 1997 | Experimental study |
Citations in the library
Cited by 2
- Deciphering the allosteric landscape of 5-HT2 receptors: integrated molecular dynamics and fragment molecular orbital analyses of activation mechanisms Pharmacological Reports September 25, 2026
- Exploring a Druggable Hydrophobic Tunnel in the 5-HT2A Receptor with Potent Phenethylamines Journal of Medicinal Chemistry September 25, 2026
Cites 12
- Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential. Nature Communications December 15, 2023
- A non-hallucinogenic LSD analog with therapeutic potential for mood disorders. Cell Reports March 28, 2023
- Synthesis and structure-activity relationships of N-benzyl phenethylamines as 5-HT2A/2C agonists. ACS Chemical Neuroscience March 19, 2014
- Effect of Hallucinogens on Unconditioned Behavior Current Topics in Behavioral Neurosciences 2016
- Beyond the 5-HT2A Receptor: Classic and Nonclassic Targets in Psychedelic Drug Action. Journal of Neuroscience November 8, 2023
and 7 more in the library