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However, the central role that the biogenic amine binding GPCRs and their ligands play in cell signaling poses a risk in new drug candidates that reveal side affinities towards these receptor sites. These candidates have the potential to interfere with the physiological signaling processes and to cause undesired effects in preclinical or clinical studies. Here, we present 3D cross\u2010chemotype pharmacophore models for three biogenic amine antitargets: the \u03b1<\/jats:italic><jats:sub><jats:italic>1A<\/jats:italic><\/jats:sub> <jats:italic>adrenergic, the 5\u2010HT<\/jats:italic><jats:sub><jats:italic>2A<\/jats:italic><\/jats:sub> <jats:italic>serotonin, and the D2 dopamine receptors. These pharmacophores describe the key chemical features present within these biogenic amine antagonists and rationalize the biogenic amine side affinities found for numerous new drug candidates. First applications of the \u03b1<\/jats:italic><jats:sub><jats:italic>1A<\/jats:italic><\/jats:sub> <jats:italic>adrenergic receptor model reveal that these in silico tools can be used to guide the chemical optimization towards development candidates with fewer \u03b1<\/jats:italic><jats:sub><jats:italic>1A<\/jats:italic><\/jats:sub><jats:italic>\u2010mediated side effects (for example, orthostatic hypotension) and, thus, with an improved clinical safety profile.<\/jats:italic><\/jats:p>","DOI":"10.1002\/cbic.200400369","type":"journal-article","created":{"date-parts":[[2005,3,24]],"date-time":"2005-03-24T11:32:10Z","timestamp":1111663930000},"page":"876-889","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":81,"title":["GPCR Antitarget Modeling: Pharmacophore Models for Biogenic Amine Binding GPCRs to Avoid GPCR\u2010Mediated Side Effects"],"prefix":"10.1002","volume":"6","author":[{"given":"Thomas","family":"Klabunde","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Evers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2005,4,22]]},"reference":[{"key":"e_1_2_6_1_2","doi-asserted-by":"publisher","DOI":"10.1002\/1439-7633(20021004)3:10<928::AID-CBIC928>3.0.CO;2-5"},{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0893-133X(98)00072-4"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/0028-3908(77)90023-5"},{"key":"e_1_2_6_4_2","unstructured":"Aureus Pharma:www.aureus\u2010pharma.com."},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1358\/dnp.2003.16.2.829326"},{"key":"e_1_2_6_6_2","unstructured":"Catalyst Version 4.7 Accelrys Inc. 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