View source for 8zmf


==Crystal structure of an inverse agonist antipsychotic drug derivative-bound 5-HT2C==
<StructureSection load='8zmf' size='340' side='right'caption='[[8zmf]], [[Resolution|resolution]] 3.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8zmf]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8ZMF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8ZMF FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.6&#8491;</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8zmf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8zmf OCA], [https://pdbe.org/8zmf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8zmf RCSB], [https://www.ebi.ac.uk/pdbsum/8zmf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8zmf ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/C562_ECOLX C562_ECOLX] Electron-transport protein of unknown function.[https://www.uniprot.org/uniprot/5HT2C_HUMAN 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.<ref>PMID:12970106</ref> <ref>PMID:18703043</ref> <ref>PMID:19057895</ref> <ref>PMID:7895773</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Psychosis 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<ref>PMID:39137033</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8zmf" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Escherichia coli]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Asada H]]
[[Category: Imono M]]
[[Category: Iwata S]]
[[Category: Kusakabe K]]
[[Category: Oguma T]]
[[Category: Sekiguchi Y]]