The pharmacological profile of tobacco alkaloids is essential for understanding their physiological effects. Nicotinic acetylcholine receptors (nAChRs) are an important target of tobacco alkaloids with primarily agonistic effects reported for \u03b14\u03b22 nAChRs, but with minimal evidence of \u03b17 activity. In this study, we used a membrane potential assay and automated patch-clamp electrophysiological approaches to functionally characterize distinct groups of tobacco alkaloids in the presence of a subunit-specific positive allosteric modulator (PAM) of human \u03b14\u03b22 and \u03b17 nAChRs. We screened a total of 71 tobacco alkaloids, of which 16 were active against \u03b14\u03b22 and 11 against \u03b17 nAChRs.<\/p>\n
The most abundant alkaloids in tobacco leaves\u2014namely nicotine, nornicotine, anabasine, (S)-anatabine, and (R)-anatabine\u2014exhibited potencies (EC50<\/sub>alkaloid+PAM) of 0.02-20 \u03bcM against \u03b14\u03b22 and 0.2-10 \u03bcM against \u03b17 nAChRs. In the presence of the PAM, nicotine and anabasine, respectively, were found to be the most potent \u03b14\u03b22 and \u03b17 nAChRs agonists. Relative to (S)-anatabine, (R)-anatabine was 5-fold more potent against \u03b14\u03b22; the relationship was found to be inverse in case of \u03b17 nAChRs. In addition, 13 alkaloids demonstrated agonistic effects only in the presence of the PAM and were, therefore, considered to be silent agonists. In conclusion, the data revealed 17 naturally occurring tobacco alkaloids that exhibited a dramatic increase in potency against human \u03b14\u03b22 and \u03b17 nAChRs in the presence of PAMs (relative to that in the absence of the PAM). Our study recognized a subunit-specific enantiomer preference of anatabine and identified several alkaloids with silent agonist properties for human \u03b14\u03b22 and \u03b17 nAChRs.<\/p>\n","protected":false},"featured_media":0,"template":"","products_tags":[44],"resource_type":[320],"application_areas":[],"therapeutic_areas":[],"target_categories":[],"target_families":[],"targets":[],"resource_keyword":[],"class_list":["post-7152","resource_library","type-resource_library","status-publish","hentry","products_tags-patchliner","resource_type-webinar"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_library\/7152","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_library"}],"about":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/types\/resource_library"}],"wp:attachment":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/media?parent=7152"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/products_tags?post=7152"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_type?post=7152"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/application_areas?post=7152"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/therapeutic_areas?post=7152"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_categories?post=7152"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_families?post=7152"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/targets?post=7152"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_keyword?post=7152"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}