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It displays favorable pharmacokinetic and in vitro safety profiles, and served as a lead compound in a program to explore ergoline derivatives as potential drug candidates for the treatment of narcolepsy. A key objective of this work was to enhance the safety and efficacy profiles of <jats:bold>1<\/jats:bold>, while minimizing its duration of action to mitigate the episodes of insomnia documented with previously reported clinical candidates during the night following administration. Modifications to the ergoline core at positions\u20051, 6 and 8 were systematically investigated, and derivative <jats:bold>23<\/jats:bold> (1\u2010((4a<jats:italic>R<\/jats:italic>,8<jats:italic>R<\/jats:italic>,9a<jats:italic>R<\/jats:italic>)<jats:italic>\u2010<\/jats:italic>8\u2010(hydroxymethyl)\u20101\u2010(2\u2010((<jats:italic>R<\/jats:italic>)\u20102\u2010methylpyrrolidin\u20101\u2010yl)ethyl)\u20104,4a,7,8,9,9a\u2010hexahydroindolo[1,14\u2010fg]quinolin\u20106(1<jats:italic>H<\/jats:italic>)\u2010yl)ethanone) was identified as a promising lead compound. Derivative <jats:bold>23<\/jats:bold> has a desirable pharmacokinetic profile and demonstrated efficacy by enhancing brain concentrations of tele\u2010methylhistamine, a major histamine metabolite. This validates the potential of the ergoline scaffold to serve as a template for the development of H3R inverse agonists.<\/jats:p>","DOI":"10.1002\/cmdc.201402055","type":"journal-article","created":{"date-parts":[[2014,5,21]],"date-time":"2014-05-21T16:30:56Z","timestamp":1400689856000},"page":"1683-1696","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Ergoline\u2010Derived Inverse Agonists of the Human H3 Receptor for the Treatment of Narcolepsy"],"prefix":"10.1002","volume":"9","author":[{"given":"Yves P.","family":"Auberson","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Troxler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuechun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles R.","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Markus","family":"Fendt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dominik","family":"Feuerbach","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu\u2010Chih","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bharat","family":"Lagu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Lerchner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Perrone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lijun","family":"Lei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunxiu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tie\u2010Lin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark G.","family":"Bock","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2014,5,21]]},"reference":[{"key":"e_1_2_6_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/302832a0"},{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.55.6.1101"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm100064d"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0062743"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0907006"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)00058-1"},{"key":"e_1_2_6_6_3","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)00058-1"},{"key":"e_1_2_6_7_2","first-page":"9","author":"Nishino S.","year":"2007","journal-title":"J. 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