{"refrec":{"BRefID":256987,"RR":"<b>Jukic, M.; Frlan, R.; Chan, F.; Kirby, R.; Madge, D.; Tytgat, J.; Peigneur, S.; Anderluh, M.; Kikelj, D.</b> (2015). Synthesis and biological evaluation of piperazine derivatives as novel isoform selective voltage-gated sodium (Na<sub>v</sub>) 1.3 channel modulators. <i>Med. Chem. Res. 24(6)</i>: 2366-2380. <a href=\"http://dx.doi.org/10.1007/s00044-014-1300-x\" target=\"_blank\">dx.doi.org/10.1007/s00044-014-1300-x</a>","BEntID":248996,"PublicFlag":1,"CheckedFlag":1,"wosflag":1,"vabbflag":1,"RefStringPartII":". <i>Med. Chem. Res. 24(6)</i>: 2366-2380. <a href=\"https://dx.doi.org/10.1007/s00044-014-1300-x\" target=\"_blank\">https://dx.doi.org/10.1007/s00044-014-1300-x</a>","DocTypID":8,"DocType":"Journal article","MarineFlag":1,"FreshFlag":0,"BrackishFlag":0,"TerrestrialFlag":0,"Authorstring":"Jukic, M.; Frlan, R.; Chan, F.; Kirby, R.; Madge, D.; Tytgat, J.; Peigneur, S.; Anderluh, M.; Kikelj, D.","OrigTitleTranslFlag":0,"Authorstringtrunc":"Jukic, M. <i>et al.</i>","Englishabstract":"Sponges of the genus Agelas produce compounds that modulate the activity of voltage-gated sodium ion channels and contribute novel scaffolds for the development of compounds with activity against a plethora of biological targets. In particular, clathrodin and dibromosceptrin were reported to decrease the average maximum amplitude of inward sodium currents in isolated chick embryo sympathetic ganglia cells; we envisaged these compounds as a starting point to design novel Na-v channel modulators. This endeavor was part of our long-term goal of designing a comprehensive library of Agelas alkaloid analogs that would cover a broader chemical space and allow us to examine the activity of such compounds on Na-v channels. Our series of compounds was designed by maintaining the terminal structural features found in clathrodin while rigidizing the central part of the molecule and replacing the 3-aminopropene linker with a 4-methylenepiperazine moiety. Synthesised compounds were screened for inhibitory action against the human voltage-gated sodium channel isoforms Na-v 1.3, Na-v 1.4, cardiac Na-v 1.5, and Na-v 1.7 using an automated patch clamp electrophysiology technique. The results demonstrate that we have obtained a series of compounds with a modest but selective inhibitory activity against the Na-v 1.3 channel isoform. The most potent compound showed selective activity against the Na-v 1.3 channel isoform with an IC50 of 19 mu M and is a suitable starting point for further development of selective Na-v 1.3 channel modulators. Such compounds could prove to be beneficial as a pharmacological tool towards the development of novel therapeutically useful compounds in the treatment of pain.","AbstractOtherLang":null,"BibLvlCode":"AS","StandardTitle":"Synthesis and biological evaluation of piperazine derivatives as novel isoform selective voltage-gated sodium (Na<sub>v</sub>) 1.3 channel modulators","OrigTitleLangCode":"en","OrigTitleLangCodeExtended":"eng","OrigTitleLangID":15,"DateLastModified":{"date":"2024-12-10 01:33:17.368041","timezone_type":1,"timezone":"+01:00"},"UserAccessRight":null,"UserAccID":null,"AuthorKeywords":"Voltage-gated; Sodium channels; Na-v channels; Na-v channel modulators;Isoform selective modulators; Piperazine derivatives","OtherDescriptors":null,"Notes":null,"AnaPub":2015,"MonPub":null,"DateUpdate":"2016-06-20","DateCreate":"2016-05-29","SecASFANote":null,"ConfID":null,"PeerRev":1,"VlizCoreFlag":1,"WoScode":"WOS:000355933000008","VABBcode":null,"OpenAcc":0,"DOI":"10.1007/s00044-014-1300-x"},"refs":null,"anarec":{"AnaID":256987,"PubliDate":2015,"Pagination":"2366-2380","XtraPublOfAnaID":null,"ISBN":null,"Volume":"24","Issue":"6","BRefMon":null,"BRefMonRR":null,"BRefXtra":null,"BRefXtraRR":null,"SerBRefID":259098,"SerRR":"Medicinal Chemistry Research. 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