[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-1-en-105":3,"doc-seo-189345-105":53,"doc-detail-189345-en":126},{"code":4,"msg":5,"data":6},0,"success",[7,14,19,24,29,34,39,44,49],{"id":8,"doc_module":9,"doc_module_name":10,"category_name":11,"show_sort_weight":12,"slug":13},11,1,"Template","Presentations",90,"presentations",{"id":15,"doc_module":9,"doc_module_name":10,"category_name":16,"show_sort_weight":17,"slug":18},12,"Resumes",80,"resumes",{"id":20,"doc_module":9,"doc_module_name":10,"category_name":21,"show_sort_weight":22,"slug":23},14,"Invoices",70,"invoices",{"id":25,"doc_module":9,"doc_module_name":10,"category_name":26,"show_sort_weight":27,"slug":28},15,"Posters",60,"posters",{"id":30,"doc_module":9,"doc_module_name":10,"category_name":31,"show_sort_weight":32,"slug":33},16,"Social Media",50,"social-media",{"id":35,"doc_module":9,"doc_module_name":10,"category_name":36,"show_sort_weight":37,"slug":38},17,"Forms",40,"forms",{"id":40,"doc_module":9,"doc_module_name":10,"category_name":41,"show_sort_weight":42,"slug":43},18,"Letters",30,"letters",{"id":45,"doc_module":9,"doc_module_name":10,"category_name":46,"show_sort_weight":47,"slug":48},21,"Paper Templates",5,"papers-templates",{"id":50,"doc_module":9,"doc_module_name":10,"category_name":51,"show_sort_weight":4,"slug":52},158,"General","general-158",{"code":4,"msg":54,"data":55},"ok",{"site_id":56,"language":57,"slug":58,"title":59,"keywords":60,"description":61,"schema_data":62,"social_meta":119,"head_meta":121,"extra_data":123,"updated_unix":125},105,"en","metoclopramide-a-template-for-drug-discovery","Metoclopramide: A Template for Drug Discovery","","Metoclopramide, first described in 1964 as an anti-emetic and gastrointestinal motility stimulant, is explained through dopamine D2 receptor antagonism and linked to the prevention of emesis during anticancer chemo-radiotherapy. When platinum-based cancer drugs caused severe, treatment-limiting emesis, higher metoclopramide doses inhibited this effect whereas higher doses of other D2 antagonists failed. Mechanistic studies using ferrets highlighted roles for 5-HT3 receptor antagonism in cisplatin-induced emesis, and a D2- and 5-HT3-independent pathway for GI motility later attributed to the 5-HT4 receptor, shaping multiple therapeutic drug classes.",{"@graph":63,"@context":118},[64,80,101],{"@type":65,"itemListElement":66},"BreadcrumbList",[67,71,74,77],{"item":68,"name":69,"@type":70,"position":9},"https://docshare.wps.com","Home","ListItem",{"item":72,"name":10,"@type":70,"position":73},"https://docshare.wps.com/template/",2,{"item":75,"name":51,"@type":70,"position":76},"https://docshare.wps.com/template/general/",3,{"item":78,"name":59,"@type":70,"position":79},"https://docshare.wps.com/template/metoclopramide-a-template-for-drug-discovery/189345/",4,{"url":78,"name":59,"@type":81,"image":82,"author":87,"headline":59,"publisher":90,"fileFormat":93,"inLanguage":57,"description":61,"dateModified":94,"datePublished":95,"encodingFormat":93,"isAccessibleForFree":96,"interactionStatistic":97},"DigitalDocument",{"url":83,"@type":84,"width":85,"height":86},"https://docshare.wps.com/thumbnails/metoclopramide-a-template-for-drug-discovery/189345.png","ImageObject",442,249,{"name":88,"@type":89},"Caleb Sterling","Person",{"url":68,"name":91,"@type":92},"DocShare","Organization","application/pdf","2026-09-23","2026-09-03",true,{"@type":98,"interactionType":99,"userInteractionCount":47},"InteractionCounter",{"@type":100},"ViewAction",{"@type":102,"mainEntity":103},"FAQPage",[104,110,114],{"name":105,"@type":106,"acceptedAnswer":107},"How did metoclopramide initially get connected to its anti-emetic activity?","Question",{"text":108,"@type":109},"Its anti-emetic action was initially attributed to dopamine D2 receptor antagonism, which also suggested stimulation of gastrointestinal motility.","Answer",{"name":111,"@type":106,"acceptedAnswer":112},"Why did higher doses of metoclopramide help when platinum-based therapies caused severe emesis?",{"text":113,"@type":109},"Higher doses inhibited the debilitating, days-long emesis, while subsequent trials using higher doses of other D2 receptor antagonists were unsuccessful.",{"name":115,"@type":106,"acceptedAnswer":116},"What receptor mechanisms explain metoclopramide’s effects on GI motility and emesis?",{"text":117,"@type":109},"Research replicated findings in ferrets and showed that 5-HT3 receptor antagonists could inhibit cisplatin-induced emesis. Separately, stimulation of GI motility was shown to be independent of D2 and 5-HT3 antagonism and was later characterized as involving the 5-HT4 receptor.","https://schema.org",{"og:url":78,"og:type":120,"og:title":59,"og:site_name":91,"og:description":61},"article",{"robots":122,"canonical":78},"index,follow",{"doc_id":124,"site_id":56},189345,1788396140,{"code":4,"msg":5,"data":127},{"doc_id":124,"user_id":128,"nickname":88,"user_avatar":129,"doc_module":9,"category_id":50,"category_name":51,"doc_title":59,"doc_description":61,"doc_content":130,"file_id":131,"file_url":132,"file_type":133,"file_size":134,"view_count":47,"is_deleted":4,"is_public":9,"is_downloadable":9,"audit_status":9,"page_count":135,"language":136,"language_code":57,"site_id":56,"html_lang":57,"table_of_contents":137,"faqs":138,"seo_title":139,"seo_description":61,"update_tm":125,"read_time":73},962084925290,"https://ap-avatar.wpscdn.com/davatar_085a072bc5b1113ac321206ff7593b45","| Research Article |  | *Corresponding author\u003Cbr>Gareth J Sanger, Blizard Institute and the National |\n| --- | --- | --- |\n| Metoclopramide: A Template for |  | Centre for Bowel Research, Barts & The London School of Medicine and Dentistry, Queen Mary University of London, UK, Email: g |\n| Drug Discovery |  | Submitted: 20 October 2016\u003Cbr>Accepted: 16 December 2016\u003Cbr>Published: 02 January 2017 |\n| Gareth J Sanger* |  | ISSN: 2379-089X |\n| Blizard Institute and the National Centre for Bowel Research, Barts & The London School of Medicine and Dentistry, Queen Mary University of London, UK |  | Copyright\u003Cbr>© 2017 Sanger |\n| Abstract\u003Cbr>Metoclopramide was described in 1964 as an anti-emetic drug and stimulant of gastrointestinal motility. Dopamine D2 receptor antagonism explained the anti-emetic activity and was suggested to stimulate gastrointestinal motility. An important use of metoclopramide and other D2 receptor antagonists is to inhibit emesis caused by anticancer chemo radiotherapy. However, the use of new platinum-based anti-cancer drugs led to debilitating emesis, lasting for days and sometimes leading to refusal of treatment. Unlike conventional doses, higher doses of metoclopramide inhibited this severe emesis whereas subsequent trials with higher doses of other D2 receptor antagonists were unsuccessful. Studies using ferrets replicated these findings and then demonstrated the ability of 5-HT3 receptor antagonists to inhibit cisplatin-induced emesis, correlating with the known ability of higher concentrations of metoclopramide to antagonise at this receptor. Around the same time, the mechanism by which metoclopramide stimulates GI motility was shown to be independent of D2 and 5-HT3 receptor antagonism. A‘myenteric 5-HT-like receptor’ was proposed, mediating the ability of metoclopramide to facilitate GI cholinergic activity. Later, this was characterised as the 5-HT4 receptor. Extensive drug discovery followed the unravelling of the biology of metoclopramide. The serendipitous discovery of this drug has therefore contributed to development of three new drug classes: selective (peripherally-restricted) antagonists at D2 and 5-HT3 receptors and selective agonists at the 5-HT4 receptor. The latter are used to treat idiopathic constipation. 5-HT3 receptor antagonists, together with dexamethasone and if necessary, NK1 receptor antagonists, prevent moderate-to-severe emesis during anti-cancer treatment and hence, began a revolution in cancer patient care. The ability of 5-HT3 receptor antagonists to cause mild constipation was used to treat diarrhoeapredominant irritable bowel syndrome, achieving clinical success but later associated with severe adverse events. Antagonists at the D2 receptor treat mild forms of emesis. Metoclopramide is still used as a gastric prokinetic and anti-emetic drug. |  | \u003Cbr>OPEN ACCESS\u003Cbr>Keywords\u003Cbr>• Metoclopramide\u003Cbr>• Dopamine D2 receptor\u003Cbr>• 5-HT4 receptor\u003Cbr>• 5-HT3 receptor\u003Cbr>• Drug discovery\u003Cbr>• Emesis |\n| INTRODUCTION\u003Cbr>Metoclopramide was synthesised during a programme aimed at improving on the properties of procainamide, a cardiac antiarrhythmic and local anaesthetic drug which was itself derived from procaine (conversion of the ester to the amide linking the benzamide ring and the side chain of procaine gave procainamide, resistant to breakdown by esterases) . Further substitution of the benzene ring created metoclopramide, a compound with surprising anti-emetic properties [1-3](Table) .\u003Cbr>Unlike procainamide, metoclopramide had negligible local anaesthetic or cardiac anti-arrhythmic activity [4] . Antiemetic activity was demonstrated against different emetic stimuli, including apomorphine, a dopamine receptor agonist [5] . Subsequently, metoclopramide was found to increase gastrointestinal (GI) motility and reduce symptoms associated with various upper GI disorders [6]. Atthe time the mechanisms of these actions were unclear, but it was known that the drug could | act as a dopam","cbCaifEoJDguJyye","https://ap.wps.com/l/cbCaifEoJDguJyye","pdf",1104634,6,"English","# Abstract\n# Introduction\n## Drug synthesis and early observations\n## Established receptor mechanisms\n## Clinical implications and therapeutic impact","[{\"question\":\"How did metoclopramide initially get connected to its anti-emetic activity?\",\"answer\":\"Its anti-emetic action was initially attributed to dopamine D2 receptor antagonism, which also suggested stimulation of gastrointestinal motility.\"},{\"question\":\"Why did higher doses of metoclopramide help when platinum-based therapies caused severe emesis?\",\"answer\":\"Higher doses inhibited the debilitating, days-long emesis, while subsequent trials using higher doses of other D2 receptor antagonists were unsuccessful.\"},{\"question\":\"What receptor mechanisms explain metoclopramide’s effects on GI motility and emesis?\",\"answer\":\"Research replicated findings in ferrets and showed that 5-HT3 receptor antagonists could inhibit cisplatin-induced emesis. Separately, stimulation of GI motility was shown to be independent of D2 and 5-HT3 antagonism and was later characterized as involving the 5-HT4 receptor.\"}]","Metoclopramide: A Template for Drug Discovery | PDF"]