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As potential ocular hypotensive agents, we studied compounds that act on two receptors (serotonin 2A and adrenergic \u03b1<jats:sub>1<\/jats:sub>) linked to the regulation of aqueous humour dynamics. Herein we describe the design, synthesis, and pharmacological profiling of a series of novel bicyclic and tricyclic <jats:italic>N<\/jats:italic>2\u2010alkyl\u2010indazole\u2010amide derivatives. This study identified a 3,4\u2010dihydropyrazino[1,2\u2010<jats:italic>b<\/jats:italic>]indazol\u20101(2<jats:italic>H<\/jats:italic>)\u2010one derivative with potent serotonin 2A receptor antagonism, &gt;100\u2010fold selectivity over other serotonin subtype receptors, and high affinity for the \u03b1<jats:sub>1<\/jats:sub> receptor. Moreover, upon local administration, this compound showed superior ocular hypotensive action in\u2005vivo relative to the clinically used reference compound timolol.<\/jats:p>","DOI":"10.1002\/cmdc.201800199","type":"journal-article","created":{"date-parts":[[2018,6,6]],"date-time":"2018-06-06T07:39:45Z","timestamp":1528270785000},"page":"1597-1607","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Targeting Serotonin 2A and Adrenergic \u03b1<sub>1<\/sub> Receptors for Ocular Antihypertensive Agents: Discovery of 3,4\u2010Dihydropyrazino[1,2\u2010<i>b<\/i>]indazol\u20101(2<i>H<\/i>)\u2010one Derivatives"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6715-9919","authenticated-orcid":false,"given":"Guido","family":"Furlotti","sequence":"first","affiliation":[{"name":"Angelini RR&amp;D (Research, Regulatory &amp; Development) Angelini S.p.A.  Piazzale della stazione snc 00071 S. 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