Home Medizin Wissenschaftler entwickeln nicht-halluzinogene psychedelische Behandlungen, die möglicherweise die Erforschung der Vorteile für die psychische Gesundheit beschleunigen

Wissenschaftler entwickeln nicht-halluzinogene psychedelische Behandlungen, die möglicherweise die Erforschung der Vorteile für die psychische Gesundheit beschleunigen

von NFI Redaktion

An ongoing study published in Nature Communications has identified 5-Hydroxytryptamine 2A (5-HT2A) receptor (5-HT2AR) signaling pathways associated with psychedelic potential.


Study: Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential. Image Credit: SynthEx/Shutterstock.com









Study: Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential. Image Credit: SynthEx/Shutterstock.com

Background

Interest in classical or serotonergic psychedelics has increased due to their potential to induce rapid and sustained therapeutic effects. However, their hallucinogenic effects are limiting and can cause confusion and anxiety. While a recent preclinical study suggests the possibility of separating psychedelics from their therapeutic properties, it remains unclear which signaling pathways and receptors mediate psychedelic effects.

Serotonergic psychedelics are derivatives of various chemical structures, including lysergamides, tryptamines, and phenethylamines, all of which activate the G-protein-coupled receptor (GPCR) 5-HT2AR. GPCR-targeting ligands stabilize certain receptor conformations and energetically favor coupling to transducer proteins.

Therefore, ligand-dependent bias affects clinical pharmacology and drug development. Current psychedelics activate both β-arrestin2 and Gq via 5-HT2AR; however, the contribution of these pathways to mediating psychedelic effects is uncertain. While there are non-psychedelic agonists of 5-HT2AR, there is no explanation for the lack of psychedelic effects.

The Study and Results

In the present study, researchers developed 5-HT2AR-biased agonists to decipher a molecular and mechanistic explanation for biased 5-HT2AR agonism. First, they demonstrated that 5-HT2AR is strongly coupled to arrestin2, Gq/11, G-protein subtypes, and β-arrestin 1. Next, they tested classical psychedelics for their effects on Gq dissociation and recruitment of β-arrestin 2.

Psychedelics exhibited dynamic, time-dependent activity profiles, which in some cases surpassed the activity of the endogenous agonist 5-HT at longer time points. The effects of all tested psychedelics on β-arrestin and Gq activity were comparable at equal time points, reflecting the endogenous agonist. Additionally, not all psychedelics showed a preference for β-arrestin 2 or Gq, indicating that they were not biased toward either transducer.

Next, the team aimed to develop biased agonists to probe 5-HT2AR-coupled signaling pathways with psychedelic potential. They focused on the phenethylamine scaffold and selected 25N as the core. The researchers confirmed it to be an effective, high-affinity 5-HT2AR agonist with weak selectivity for 5-HT2CR and 5-HT2AR over 5-HT2BR.

N-benzylating 25N produced 25N-NB, which significantly reduced 5-HT2AR efficacy, but 25N-NB retained effective 5-HT2CR activity. Furthermore, the team synthesized several analogs of 25N-NB to modify the electrostatic properties of the N-benzyl ring. They observed that increasing electron density around the C5′ position of the ring enhanced 5-HT2AR affinity and agonist potency, leading to the discovery of several highly affine 5-HT2AR agonists.

Substitutions at the N-benzyl-2-position were investigated for their effects on 5-HT2AR selectivity. Bulkier/larger 2-iodo or 2-bromine substituents on the ring, reduced 5-HT2BR and 5-HT2CR activities, but retained potent 5-HT2AR activity, increasing 5-HT2AR selectivity. 25N-NBI was the most selective 5-HT2AR agonist from this series, and several tests confirmed its high selectivity. Moreover, 25N-NBI elicited a head-twitch response (HTR) in mice, confirming its psychedelic potential.

However, 25N-NBI did not show a preference for Gq or β-arrestin 2 activity. Therefore, the team focused on 25N-NB-2-OH-3-Me, another 25N analog with the highest affinity for 5-HT2AR. This compound showed a selective decrease in Gq efficacy, but not β-arrestin 2 efficacy, suggesting that steric effects around the 3-position on the ring could influence biased 5-HT2AR agonism.

Furthermore, the team explored whether Gq signaling could be further reduced by replacing the N-benzyl ring with N-biphenyl (25N-NBPh) or naphthyl ring (25N-N1-Nap). Interestingly, both 25N-NBPh and 25N-N1-Nap significantly reduced Gq efficacy but preserved β-arrestin 2 efficacy. These analogs had significantly weaker Gq and β-arrestin 2 activities at 5-HT2BR and 5-HT2CR.

Furthermore, binding assays showed that these compounds exhibited weak affinities to other 5-HT receptors and off-targets. Additional analyses indicated that β-arrestin 2-dependent agonists of the 25N series (25N-NB-2-OH-3-Me, 25N-NBPh, and 25N-N1-Nap) could not induce HTR in mice. Additional experiments showed that a certain threshold of Gq activation was required for psychedelic-like effects, and that 5-HT2AR-Gq signaling was necessary for HTR and psychedelic potential.

Next, the team investigated whether 25N-NBPh and 25N-N1-Nap could induce β-arrestin 2-dependent receptor internalization. Both compounds led to strong internalization. In contrast, Pimavanserin, a 5-HT2AR antagonist/inverse agonist, could not induce receptor internalization. Additionally, repeated administration of 25N-N1-Nap induced tachyphylaxis.

Conclusions

In conclusion, the researchers demonstrated that a rational, structure-based design could contribute to the development of 5-HTR-selective compounds. They showed that various structural and chemical properties of psychedelics could be leveraged to refine 5-HT2AR activity. The ability of 5-HT2AR agonists to induce HTR correlated with Gq activation but not recruitment of β-arrestin 2.

While β-arrestin 2-dependent agonists could not induce psychedelic-like behavioral effects, they blocked psychedelic-like behaviors in vivo. Specifically, the results suggested that a specific Gq activity threshold was required for psychedelic-like effects, which could predict psychedelic potential. Overall, the results have implications for understanding the neurobiological basis of psychedelic effects.

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