Serotonin 2A Receptor (5-HT_2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants

Abstract

Psychedelics make up a group of psychoactive compounds that induce hallucinogenic effects by activating the serotonin 2A receptor (5-HT 2A R). Clinical trials have demonstrated the traditional psychedelic substances like psilocybin as a class of rapid-acting and long-lasting antidepressants. However, there is a pressing need for rationally designed 5-HT 2A R agonists that possess optimal pharmacological profiles in order to fully reveal the therapeutic potential of these agonists and identify safer drug candidates devoid of hallucinogenic effects. This Perspective provides an overview of the structure−activity relationships of existing 5-HT 2A R agonists based on their chemical classifications and discusses recent advancements in understanding their molecular pharmacology at a structural level. The encouraging clinical outcomes of psychedelics in depression treatment have sparked drug discovery endeavors aimed at developing novel 5-HT 2A R agonists with improved subtype selectivity and signaling bias properties, which could serve as safer and potentially nonhallucinogenic antidepressants. These efforts can be significantly expedited through the utilization of structure-based methods and functional selectivity-directed screening.

G protein-specific mechanisms in the serotonin 5-HT2A receptor regulate psychosis-related effects and memory deficits

“…5A, B ): (i) a salt bridge with D3.32 and (ii) a hydrophobic sandwich formed of V3.33, F6.51 and F6.52. In fact, these positions have been corroborated by numerous mutational studies for tryptamine, 5-hydroxytryptamine and other closely related derivatives (i.e., V3.33 36 , F6.51, and F6.52 37 – 39 ). With this central scaffold in place, extension in position 5, as observed in OTV1 (1,4 benzodioxin) and OTV2 (phenoxy), are oriented towards the extracellular loop 2 (ECL2) where they result in increased contact frequencies (Fig.…”

Discovery and Structure–Activity Relationships of 2,5-Dimethoxyphenylpiperidines as Selective Serotonin 5-HT2A Receptor Agonists

“…Encouraged by the profile of 6 eu , we set out to investigate whether the structure–activity relationships of 2,5-dimethoxyphenethylamines (2C-X family) would translate to the corresponding phenylpiperidine series. In the first series of analogues we probed the effects of various substituents in the 4-position, including other halogens, trifluoromethyl (TFM), nitrile, alkyl (methyl, ethyl, and n -butyl), and thioalkyl (methyl-, ethyl-, and isopropylthio) substituents, as several of the corresponding 2C-Xs have been reported to be significantly more potent than their 4-bromo-substituted analogues . The structures and functional properties of these analogues at 5-HT 2A R and 5-HT 2C R in the Ca 2+ /Fluo-4 assay are given in Table .…”

“…In addition to their 5-HT 2A R agonist activity, classical psychedelics target numerous other serotonin receptor subtypes and in some cases other monoaminergic receptors as well. , While their shared 5-HT 2A R agonism is believed to be responsible for their acute psychedelic effects, the persistent therapeutic benefits following a single administration of these drug are yet to be causally linked to activation of 5-HT 2A R. , Thus, it remains an open question whether the broad activity profiles of the classical psychedelics are required for therapeutic efficacy. This conundrum has in recent years spawned significant research efforts aimed at developing selective 5-HT 2A R agonists to probe their possible therapeutic applications …”

“…Investigations into receptor–ligand interactions of phenethylamines have guided the design of new ligands and provided information about the importance of the ethylamine chain conformation in relation to their 5-HT 2A R activity. , The functional properties of conformationally restricted 2C-X analogues like ( R )-(3-bromo-2,5-dimethoxybicyclo­[4.2.0]­octa-1,3,5-trien-7-yl)­methanamine (TCB-2) ( 2 ) and (1 R ,2 S )-2-(4-bromo-2,5-dimethoxyphenyl)­cyclopropan-1-amine (DMPCA) ( 3 ) (Figure ) show that agonist potency at 5-HT 2A R is very dependent on the spatial orientation of the ethylamine chain, ,− with bioactivity typically residing primarily in a single enantiomer of such conformationally restrained compounds, as is also the case for 4-substituted 2,5-dimethoxy amphetamines. ,, Several potent 5-HT 2A R agonists have emerged from these efforts, whereas selectivity for the 5-HT 2A R toward the other 5-HT 2 Rs remains an unresolved challenge.…”

Synthesis and bioactivity of psilocybin analogues containing a stable carbon–phosphorus bond

“…In this context, psychedelic drugs such as psilocybin, LSD, ketamine and MDMA have gained prominence as potential candidates for the treatment of psychiatric disorders. 7,8 Notably, the regulatory approvals in March and December 2019 for intranasal administration of esketamine in conjunction with a conventional antidepressant for adults suffering from TRD are evidence of the evolving landscape. 9 Completed phase 2 clinical trials show that psilocybin-assisted therapies produce large, rapid and long-lasting therapeutic effects among patients with MDD due to increased spine density and brain network integration.…”