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A non-hallucinogenic LSD analog with therapeutic potential for mood disorders

2023; Cell Press; Volume: 42; Issue: 3 Linguagem: Inglês

10.1016/j.celrep.2023.112203

2639-1856

Vern Lewis, Emma M. Bonniwell, Janelle K. Lanham, Abdi Ghaffari, Hooshmand Sheshbaradaran, Andrew B. Cao, Maggie M. Calkins, Mario Alberto Bautista-Carro, Emily Arsenault, Andre Telfer, Fatimeh‐Frouh Taghavi‐Abkuh, Nicholas J. Malcolm, Fatema El Sayegh, Alfonso Abizaid, Yasmin Schmid, Kathleen Morton, Adam L. Halberstadt, Argel Aguilar‐Valles, John D. McCorvy,

Chemical synthesis and alkaloids

Hallucinations limit widespread therapeutic use of psychedelics as rapidly acting antidepressants. Here we profiled the non-hallucinogenic lysergic acid diethylamide (LSD) analog 2-bromo-LSD (2-Br-LSD) at more than 33 aminergic G protein-coupled receptors (GPCRs). 2-Br-LSD shows partial agonism at several aminergic GPCRs, including 5-HT2A, and does not induce the head-twitch response (HTR) in mice, supporting its classification as a non-hallucinogenic 5-HT2A partial agonist. Unlike LSD, 2-Br-LSD lacks 5-HT2B agonism, an effect linked to cardiac valvulopathy. Additionally, 2-Br-LSD produces weak 5-HT2A β-arrestin recruitment and internalization in vitro and does not induce tolerance in vivo after repeated administration. 2-Br-LSD induces dendritogenesis and spinogenesis in cultured rat cortical neurons and increases active coping behavior in mice, an effect blocked by the 5-HT2A-selective antagonist volinanserin (M100907). 2-Br-LSD also reverses the behavioral effects of chronic stress. Overall, 2-Br-LSD has an improved pharmacological profile compared with LSD and may have profound therapeutic value for mood disorders and other indications.