8zmf
Crystal structure of an inverse agonist antipsychotic drug derivative-bound 5-HT2C
Structural highlights
FunctionC562_ECOLX Electron-transport protein of unknown function.5HT2C_HUMAN G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including ergot alkaloid derivatives, 1-2,5,-dimethoxy-4-iodophenyl-2-aminopropane (DOI) and lysergic acid diethylamide (LSD). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Signaling activates a phosphatidylinositol-calcium second messenger system that modulates the activity of phosphatidylinositol 3-kinase and down-stream signaling cascades and promotes the release of Ca(2+) ions from intracellular stores. Regulates neuronal activity via the activation of short transient receptor potential calcium channels in the brain, and thereby modulates the activation of pro-opiomelacortin neurons and the release of CRH that then regulates the release of corticosterone. Plays a role in the regulation of appetite and eating behavior, responses to anxiogenic stimuli and stress. Plays a role in insulin sensitivity and glucose homeostasis.[1] [2] [3] [4] Publication Abstract from PubMedPsychosis is a distressing symptom commonly occurring in people with dementia. To treat Parkinson's disease psychosis, pimavanserin (1), a 5-HT(2A) receptor inverse agonist having minimal 5-HT(2C) receptor affinity and no dopamine D(2) receptor affinity, was approved in the United States, but not for dementia-related psychosis due to limited efficacy issues. Herein, we report on the identification of a potent and dual 5-HT(2A) and 5-HT(2C) receptor inverse agonist 8 having minimal hERG inhibition, after having demonstrated the involvement of both 5-HT(2A) and 5-HT(2C) receptors to deliver antipsychotic efficacy in an MK-801-induced locomotor model and having conducted 5-HT(2A) and 5-HT(2C) occupancy studies including a surrogate method. The introduction of a spirocyclopropyl group boosting 5-HT(2C) affinity in 1 followed by further optimization to control lipophilicity resulted in balanced dual potency and metabolic stability, and mitigating hERG inhibition led to 8 that showed significant antipsychotic efficacy due to the involvement of both receptors. Dual 5-HT(2A) and 5-HT(2C) Receptor Inverse Agonist That Affords In Vivo Antipsychotic Efficacy with Minimal hERG Inhibition for the Treatment of Dementia-Related Psychosis.,Oguma T, Jino K, Nakahara K, Asada H, Fuchino K, Nagatani K, Kouki K, Okamoto R, Takai N, Koda K, Fujita S, Sekiguchi Y, Yasuo K, Mayumi K, Abe A, Imono M, Horiguchi N, Iwata S, Kusakabe KI J Med Chem. 2024 Aug 22;67(16):14478-14492. doi: 10.1021/acs.jmedchem.4c01244. , Epub 2024 Aug 13. PMID:39137033[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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