Structure-based discovery of nonhallucinogenic psychedelic analogs

Abstract

Drugs that target the human serotonin 2A receptor (5-HT 2A R) are used to treat neuropsychiatric diseases; however, many have hallucinogenic effects, hampering their use. Here, we present structures of 5-HT 2A R 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 addition to the canonical mode, which enabled the design of the psychedelic IHCH-7113 (a substructure of antipsychotic lumateperone) and several 5-HT 2A R β-arrestin–biased agonists that displayed antidepressant-like activity in mice but without hallucinogenic effects. The 5-HT 2A R complex structures presented herein and the resulting insights provide a solid foundation for the structure-based design of safe and effective nonhallucinogenic psychedelic analogs with therapeutic effects.

Effect of Psilocybin and Ketamine on Brain Neurotransmitters, Glutamate Receptors, DNA and Rat Behavior

“…On the other hand, our behavioral tests were performed 24 h after the administration of the drugs, and while that is enough to eliminate their acute effects, it might not be enough for the long-lasting effects to manifest fully, as Hibicke et al (2020) [ 26 ] reported an antidepressant effect observed 7 days post psilocybin administration. In this context, a dissenting observation was reported in the latest study of Cao et al 2022 [ 65 ], that the acute administration of LSD (30 min prior to the FST) significantly attenuated “depression-like” freezing behavior in the forced swimming test in naive mice. Taking into account the above studies, the time of test performance is critical for its outcome.…”

Discovery of β-Arrestin-Biased 25CN-NBOH-Derived 5-HT2AReceptor Agonists

“… 39 − 42 Recently, the first partial agonist ( E max = 13%) with bias toward the βarr2 over Gα q-γ9 pathway, compared to the reference 5-HT, has been disclosed (IHCH-7086). 43 However, no strongly biased agonist for the G-protein-mediated signaling pathway has been identified. Herein, we have profiled the subtype-selective agonist 25CN-NBOH and a series of close analogues for functional selectivity at 5-HT 2A R in Gα q - and βarr2-based functional assays and have evaluated the role of the simultaneous interaction of Ser159 3×36 with the ammonium and the benzylic hydroxyl of the ligands, 44 which led to the discovery of the first efficacious βarr2-biased agonists for this receptor, relative to LSD.…”

Ketamine Analgesia and Psychedelia: Can We Dissociate Dissociation?

“…11 Collectively, this line of investigation can yield important scientific contributions and is aligned with a wider trend of synthesizing nonhallucinogenic analogs of psychedelic drugs that have therapeutic potential, as has been recently done with ibogaine 12 and lysergic acid diethylamide (known widely as "LSD"). 13 In conclusion, the work of Olofsen et al 1 challenges us to take the next step in basic, translational, and clinical research. Importantly, the healthy controversy surrounding ketamine in our field is connected to a much broader and more intense dialog of whether the apparent therapeutic effects of psychedelic drugs such as psilocybin or dimethyltryptamine are necessarily linked to altered states of consciousness per se, or whether therapeutic benefit can ultimately be dissociated from dissociation and other dimensions of the psychedelic experience.…”

“…11 Collectively, this line of investigation can yield important scientific contributions and is aligned with a wider trend of synthesizing nonhallucinogenic analogs of psychedelic drugs that have therapeutic potential, as has been recently done with ibogaine 12 and lysergic acid diethylamide (known widely as “LSD”). 13…”