Biochemistry
January 21, 2022
121 citations
Psychedelic compounds can produce beneficial behavioral changes relevant to treating neuropsychiatric disorders that last long after the drugs are cleared from the body. One hypothesis for these enduring effects is that psychedelics promote structural and functional neuroplasticity in the prefrontal cortex (PFC), a brain region where neuron atrophy is a hallmark of stress-related diseases like depression, PTSD, and addiction. Psychedelics appear to be effective catalysts for regrowing these neurons and restoring synaptic connectivity. Evidence suggests the hallucinogenic effects are not directly linked to the neuroplasticity-promoting ability. Fully characterizing the molecular mechanisms of psychedelic-induced neuroplasticity is needed to develop improved alternatives. This review covers current understanding of biochemical signaling pathways activated by psychedelics and related molecules, focusing on key unanswered questions.
Biochemistry
June 21, 2005
Feng Yan, Philip D Mosier, Richard B Westkaemper et al.
91 citations
Salvinorin A, a hallucinogenic compound from the plant Salvia divinorum, selectively and potently activates kappa-opioid receptors (KORs), making it the only known lipid-like molecule to do so and the only non-nitrogenous opioid receptor agonist. Key residues in KORs responsible for its high binding affinity and agonist efficacy were identified: interactions with tyrosine residues in helix 7 (Tyr313 and Tyr320) and helix 2 (Tyr119) stabilize salvinorin A in the binding pocket, while activation requires interactions with helix 7 tyrosines Tyr312, Tyr313, and Tyr320 and with Tyr139 in helix 3.
Biochemistry
July 28, 2009
Feng Yan, Ruslan V Bikbulatov, Viorel Mocanu et al.
81 citations
Salvinorin A, the most potent naturally occurring hallucinogen, targets the kappa-opioid receptor (KOR). Researchers designed and synthesized novel irreversible salvinorin A-derived ligands, RB-64 and RB-48, as active state probes of KOR. Based on molecular modeling, they targeted cysteine residue C315(7.38) for covalent binding. Both compounds were extraordinarily potent and selective KOR agonists in vitro and in vivo. RB-64 showed wash-resistant inhibition of binding requiring a free cysteine near the binding pocket. Mass spectrometry confirmed C315(7.38) as the anchoring residue and suggested a biochemical mechanism for covalent binding. These findings provide direct evidence of a free cysteine in the agonist-bound KOR state and insights into salvinorin A's binding and activation mechanism.
Biochemistry
January 1, 1962
Thomas E. Smith, Herbert Weissbach, Sidney Udenfriend
59 citations
Monoamine oxidase (MAO) catalyzes the conversion of N,N-dimethyltryptamine (DMT) to its N-oxide form, N,N-dimethyltryptamine-N-oxide, and the reaction mechanism involves oxidative deamination. The enzyme's action on DMT proceeds through a pathway that includes the formation of an intermediate imine, which is then hydrolyzed to yield the final product. The study demonstrates that DMT-N-oxide is not a direct substrate for MAO but can be reduced back to DMT by other enzymatic systems, suggesting a potential regulatory cycle for DMT levels in tissues.
Biochemistry
February 7, 2024
5 citations
Classic psychedelics, which resemble serotonin, act on 5-HT2A receptors inside neurons. This computational study used molecular dynamics simulations to examine how 12 tryptamines cross cell membranes. Dimethylation of the amine group and a methoxy group at position 5 increased permeability. Positional substitutions on the indole ring also influenced permeation, while protonation raised the energy barrier at the bilayer center, making molecules highly impermeable. These simulation-based trends can guide future drug design for psychedelics with improved activity.