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We examined whether its action and that of other\n APDs<\/jats:styled-content>\n might be mediated by the\n GTPase<\/jats:styled-content>\n activity of dynamin. Eight of eight phenothiazine\u2010derived\n APDs<\/jats:styled-content>\n inhibited dynamin I (\n dynI<\/jats:styled-content>\n ) in the 2\u201312 \u00b5\n m<\/jats:sc>\n range, the most potent being trifluoperazine (\n \n IC\n 50<\/jats:sub>\n <\/jats:styled-content>\n 2.6 \u00b1 0.7 \u00b5\n m<\/jats:sc>\n ). They also inhibited dynamin\n II<\/jats:styled-content>\n (\n dynII<\/jats:styled-content>\n ) at similar concentrations. Typical and atypical\n APDs<\/jats:styled-content>\n not based on the phenothiazine scaffold were 8\u2010 to 10\u2010fold less potent (haloperidol and clozapine) or were inactive (droperidol, olanzapine and risperidone). Kinetic analysis showed that phenothiazine\u2010derived\n APDs<\/jats:styled-content>\n were lipid competitive, while haloperidol was uncompetitive with lipid. Accordingly, phenothiazine\u2010derived APDs inhibited\n dynI GTPase<\/jats:styled-content>\n activity stimulated by lipids but not by various\n SH3<\/jats:styled-content>\n domains. All dynamin\u2010active\n APDs<\/jats:styled-content>\n also inhibited transferrin (Tfn)\n CME<\/jats:styled-content>\n in cells at related potencies. Structure\u2013activity relationships (\n SAR<\/jats:styled-content>\n ) revealed dynamin inhibition to be conferred by a substituent group containing a terminal tertiary amino group at the\n N2<\/jats:styled-content>\n position. Chlorpromazine was previously proposed to target\n AP<\/jats:styled-content>\n \u20102 recruitment in the formation of clathrin\u2010coated vesicles (\n CCV<\/jats:styled-content>\n ). However, neither chlorpromazine nor thioridazine affected\n AP<\/jats:styled-content>\n \u20102 interaction with amphiphysin or clathrin. Super\u2010resolution microscopy revealed that chlorpromazine blocks neither clathrin recruitment by\n AP<\/jats:styled-content>\n \u20102, nor\n AP<\/jats:styled-content>\n \u20102 recruitment, showing that\n CME<\/jats:styled-content>\n inhibition occurs downstream of\n CCV<\/jats:styled-content>\n formation. Overall, potent dynamin inhibition is a shared characteristic of phenothiazine\u2010derived\n APDs<\/jats:styled-content>\n , but not other typical or atypical\n APDs<\/jats:styled-content>\n , and the data indicate that dynamin is their likely in\u2010cell target in endocytosis.\n <\/jats:p>\n \n \n <\/jats:p>","DOI":"10.1111\/tra.12272","type":"journal-article","created":{"date-parts":[[2015,2,18]],"date-time":"2015-02-18T02:53:18Z","timestamp":1424227998000},"page":"635-654","source":"Crossref","is-referenced-by-count":168,"title":["Phenothiazine\u2010Derived Antipsychotic Drugs Inhibit Dynamin and Clathrin\u2010Mediated Endocytosis"],"prefix":"10.1111","volume":"16","author":[{"given":"James A.","family":"Daniel","sequence":"first","affiliation":[{"name":"Cell Signalling Unit, Children's Medical Research Institute The University of Sydney Sydney NSW 2145 Australia"},{"name":"Present address: Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine Hermann\u2010Rein\u2010Str. 3 37075 G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ngoc","family":"Chau","sequence":"additional","affiliation":[{"name":"Cell Signalling Unit, Children's Medical Research Institute The University of Sydney Sydney NSW 2145 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed K.","family":"Abdel\u2010Hamid","sequence":"additional","affiliation":[{"name":"Centre for Chemical Biology, Chemistry The University of Newcastle Callaghan NSW 2308 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingbo","family":"Hu","sequence":"additional","affiliation":[{"name":"Epithelial Cancer Group, The University of Queensland Diamantina Institute, Translational Research Institute University of Queensland Woolloongabba QLD 4102 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"von Kleist","sequence":"additional","affiliation":[{"name":"Leibniz Institut f\u00fcr Molekulare Pharmakologie & Freie Universit\u00e4t Berlin 13125 Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ainslie","family":"Whiting","sequence":"additional","affiliation":[{"name":"Cell Signalling Unit, Children's Medical Research Institute The University of Sydney Sydney NSW 2145 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sai","family":"Krishnan","sequence":"additional","affiliation":[{"name":"Cell Signalling Unit, Children's Medical Research Institute The University of Sydney Sydney NSW 2145 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Maamary","sequence":"additional","affiliation":[{"name":"Cell Signalling Unit, Children's Medical Research Institute The University of Sydney Sydney NSW 2145 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon 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