Bespoke library docking for 5-HT2A receptor agonists with anti-depressant activity
Anat Levit Kaplan, Danielle N. Confair, Kuglae Kim, Ximena Barros-Álvarez, Ramona M. Rodriguiz, Ying Yang, O. Kweon, Tao Che, John D. Mccorvy, David N. Kamber, J. Phelan, L. C. Martins, Vladimir M Pogorelov, Jeffrey F. Diberto, Samuel T. Slocum, Xi-Ping Huang, Jain Manish Kumar, M. Robertson, Ouliana Panova, Alpay B Seven, Autumn Q. Wetsel, William C. Wetsel, John J. Irwin, Georgios Skiniotis, Brian K. Shoichet, B. Roth, J. Ellman
Nature September 28, 2022 DOI: 10.1038/s41586-022-05258-z (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Theoretical or experimental chemistry study with in vitro and mouse behavioral assays Peer reviewed |
|---|---|
| Population | Mice (behavioral assays); receptor binding and functional assays in vitro |
| Dose | as low as 1/40th of the fluoxetine dose |
| Topics | Serotonin |
| Key findings | Docking a bespoke 75-million-compound tetrahydropyridine library against the 5-HT2A receptor yielded two optimized agonists, (R)-69 and (R)-70 (EC50 41 nM and 110 nM). These compounds had high brain permeability, lacked psychedelic activity in mice, and showed antidepressant activity comparable to fluoxetine at as little as 1/40th of the dose. |
Abstract
There is considerable interest in screening ultralarge chemical libraries for ligand discovery, both empirically and computationally 1 – 4 . Efforts have focused on readily synthesizable molecules, inevitably leaving many chemotypes unexplored. Here we investigate structure-based docking of a bespoke virtual library of tetrahydropyridines—a scaffold that is poorly sampled by a general billion-molecule virtual library but is well suited to many aminergic G-protein-coupled receptors. Using three inputs, each with diverse available derivatives, a one pot C–H alkenylation, electrocyclization and reduction provides the tetrahydropyridine core with up to six sites of derivatization 5 – 7 . Docking a virtual library of 75 million tetrahydropyridines against a model of the serotonin 5-HT 2A receptor (5-HT 2A R) led to the synthesis and testing of 17 initial molecules. Four of these molecules had low-micromolar activities against either the 5-HT 2A or the 5-HT 2B receptors. Structure-based optimization led to the 5-HT 2A R agonists ( R ) - 69 and ( R ) - 70, with half-maximal effective concentration values of 41 nM and 110 nM, respectively, and unusual signalling kinetics that differ from psychedelic 5-HT 2A R agonists. Cryo-electron microscopy structural analysis confirmed the predicted binding mode to 5-HT 2A R. The favourable physical properties of these new agonists conferred high brain permeability, enabling mouse behavioural assays. Notably, neither had psychedelic activity, in contrast to classic 5-HT 2A R agonists, whereas both had potent antidepressant activity in mouse models and had the same efficacy as antidepressants such as fluoxetine at as low as 1/40th of the dose. Prospects for using bespoke virtual libraries to sample pharmacologically relevant chemical space will be considered. New agonists of the serotonin 5-HT 2A receptor (5-HT 2A R) confer high brain permeability and antidepressant activity and—in contrast to classic 5-HT 2A R agonists—lack psychedelic activity.
Comparable studies
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| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
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- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- Pilot Study of Psilocybin Treatment for Anxiety in Patients With Advanced-Stage Cancer Archives of General Psychiatry September 7, 2010
- Structural Features for Functional Selectivity at Serotonin Receptors Science March 21, 2013
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