Structure-based discovery of nonhallucinogenic psychedelic analogs

  title={Structure-based discovery of nonhallucinogenic psychedelic analogs},
  author={Dongmei Cao and Jing Yu and Huan Wang and Zhipu Luo and Xinyu Liu and Licong He and Jianzhong Qi and Luyu Fan and Lingjie Tang and Zhangcheng Chen and Jinsong Li and Jianjun Cheng and Sheng Wang},
  pages={403 - 411}
Drugs that target the human serotonin 2A receptor (5-HT2AR) are used to treat neuropsychiatric diseases; however, many have hallucinogenic effects, hampering their use. Here, we present structures of 5-HT2AR complexed with the psychedelic drugs psilocin (the active metabolite of psilocybin) and d-lysergic acid diethylamide (LSD), as well as the endogenous neurotransmitter serotonin and the nonhallucinogenic psychedelic analog lisuride. Serotonin and psilocin display a second binding mode in… 

Psychedelic compounds directly excite 5-HT2A Layer 5 Pyramidal Neurons in the Prefrontal Cortex through a 5-HT2A Gq -mediated activation mechanism

In vitro slice electrophysiology demonstrates that psilocin evokes strong firing changes in the PFC that are 5-HT2AR and Gαq dependent, thereby providing valuable insights into the effects of psilOCin on a brain region implicated in mediating psychedelic drug actions.

Tolerance and Cross-Tolerance among Psychedelic and Nonpsychedelic 5-HT2A Receptor Agonists in Mice.

Tolerance to HTR induced by psychedelics involves activation of the 5-HT2AR, is not observable upon repeated administration of nonpsychedelic 5- HT2AR agonists, and occurs via a signaling mechanism independent of β-arrestin-2.

Discovery of β-Arrestin-Biased 25CN-NBOH-Derived 5-HT2A Receptor Agonists

This work evaluated the subtype-selective 5-HT2AR agonist 25CN-NBOH and a series of close analogues for biased signaling at this receptor and designed to evaluate the role of interactions with Ser1593×36, finding that Gαq-mediated signaling was considerably more affected.

The neural basis of psychedelic action

An integrative perspective on the basic neurobiology underlying the actions of psychedelics is provided and open questions in the field are highlighted.

Bespoke library docking for 5-HT2A receptor agonists with antidepressant activity

There is considerable interest in screening ultralarge chemical libraries for ligand discovery, both empirically and computationally1–4. Efforts have focused on readily synthesizable molecules,

The promise of psychedelic research

This review will feature the incredible depth of research underway revealing how psychedelics impact brain structure and function to treat mental health and other neurological disorders.

Structure-Activity Relationships for Psilocybin, Baeocystin, Aeruginascin, and Related Analogues to Produce Pharmacological Effects in Mice.

Psilacetin appears to be a prodrug for psilocin that displays substantial serotonin receptor activities of its own, and these compounds were more potent than their 4-phosphoryloxy counterparts.

Could psychedelic drugs have a role in the treatment of schizophrenia? Rationale and strategy for safe implementation.

The possibility that psychedelic drugs could have a role in treating cortical atrophy and cell loss in schizophrenia, and ameliorating the negative symptoms associated with these pathological manifestations is considered.



A Non-Hallucinogenic Psychedelic Analog with Therapeutic Potential

This work demonstrates that, through careful chemical design, it is possible to modify a psychedelic compound to produce a safer, non-hallucinogenic variant that has therapeutic potential.

Structures of the 5-HT2A receptor in complex with the antipsychotics risperidone and zotepine

Structures of human 5- HT2AR in complex with several drugs reveal a side-extended cavity that is unique for this receptor, while molecular docking suggests that a highly 5-HT2AR-selective antagonist binds residues within this cavity.

Psychedelic-inspired drug discovery using an engineered biosensor

Ligands can induce G protein-coupled receptors (GPCRs) to adopt a myriad of conformations, many of which play critical roles in determining the activation of specific signaling cascades associated


  • D. Nichols
  • Psychology, Biology
    Pharmacological Reviews
  • 2016
Blood oxygen level–dependent functional magnetic resonance imaging and magnetoencephalography have been employed for in vivo brain imaging in humans after administration of a psychedelic, and results indicate that intravenously administered psilocybin and LSD produce decreases in oscillatory power in areas of the brain’s default mode network.

LSD’s effects are differentially modulated in arrestin knockout mice

It is found that LSD robustly stimulates many surrogates of psychedelic drug actions including head twitches, grooming, retrograde walking, and nose poking in WT and βArr1-KO animals, and that LSD’s psychedelic drug-like actions appear to require β Arr2.

Agonist-directed signaling of the serotonin 2A receptor depends on β-arrestin-2 interactions in vivo

This study suggests that the 5-HT2AR–β-arrestin interaction may be particularly important in receptor function in response to endogenous serotonin levels, which could have major implications in drug development for treating neuropsychiatric disorders such as depression and schizophrenia.

Structural determinants of 5-HT2B receptor activation and biased agonism

Four crystal structures of a prototypical serotonin receptor 5-HT2BR in complex with chemically and pharmacologically diverse drugs elucidate the structural bases for receptor activation, agonist-mediated biased signaling and β-arrestin2 translocation.

Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels

It is reported for the first time that intake of psilocybin leads to significant 5-HT2AR occupancy in the human brain, and that both psilocin plasma levels and5-HT 2AR occupancy are closely associated with subjective intensity ratings, strongly supporting that stimulation of 5- HT2AR is a key determinant for the psychedelic experience.