{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T17:42:37Z","timestamp":1760550157643},"reference-count":48,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2016,11,21]],"date-time":"2016-11-21T00:00:00Z","timestamp":1479686400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100004281","name":"National Science Centre","doi-asserted-by":"publisher","award":["UMO\u20102012\/07B\/NZ7\/01173","UMO\u20102014\/15\/B\/NZ7\/00885"],"award-info":[{"award-number":["UMO\u20102012\/07B\/NZ7\/01173","UMO\u20102014\/15\/B\/NZ7\/00885"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Archiv der Pharmazie"],"published-print":{"date-parts":[[2016,12]]},"abstract":"<jats:sec><jats:label \/><jats:p>In the search for potential psychotropic agents, a new series of 3,7\u2010dimethyl\u2010 and 1,3\u2010dimethyl\u20108\u2010alkoxypurine\u20102,6\u2010dione derivatives of arylpiperazines, perhydroisoquinolines, or tetrahydroisoquinolines with flexible alkylene spacers (<jats:bold>5<\/jats:bold>\u2013<jats:bold>16<\/jats:bold> and <jats:bold>21\u201332<\/jats:bold>) were synthesized and evaluated for 5\u2010HT<jats:sub>1A<\/jats:sub>\/5\u2010HT<jats:sub>7<\/jats:sub> receptor affinities as well as PDE4B1 and PDE10A inhibitory properties. The 1\u2010(4\u2010(4\u2010(2\u2010hydroxyphenyl)piperazin\u20101\u2010yl)butyl)\u20103,7\u2010dimethyl\u20108\u2010propoxypurine\u20102,6\u2010dione (<jats:bold>16<\/jats:bold>) and 7\u2010(2\u2010hydroxyphenyl)piperazinylalkyl\u20101,3\u2010dimethyl\u20108\u2010ethoxypurine\u20102,6\u2010diones (<jats:bold>31<\/jats:bold> and <jats:bold>32<\/jats:bold>) as potent dual 5\u2010HT<jats:sub>1A<\/jats:sub>\/5\u2010HT<jats:sub>7<\/jats:sub> receptor ligands with antagonistic activity produced an antidepressant\u2010like effect in the forced swim test in mice. This effect was similar to that produced by citalopram. All the tested compounds were stronger phosphodiesterase isoenzyme inhibitors than theophylline and theobromine. The most potent compounds, <jats:bold>15<\/jats:bold> and <jats:bold>16<\/jats:bold>, were characterized by 51 and 52% inhibition, respectively, of PDE4B1 activity at a concentration of 10<jats:sup>\u22125<\/jats:sup>\u2009M. Concerning the above findings, it may be assumed that the inhibition of PDE4B1 may impact on the signal strength and specificity resulting from antagonism toward the 5\u2010HT<jats:sub>1<\/jats:sub> and 5\u2010HT<jats:sub>7<\/jats:sub> receptors, especially in the case of compounds <jats:bold>15<\/jats:bold> and <jats:bold>16<\/jats:bold>. This dual receptor and enzyme binding mode was analyzed and explained via molecular modeling studies.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ardp.201600260","type":"journal-article","created":{"date-parts":[[2016,11,21]],"date-time":"2016-11-21T12:26:45Z","timestamp":1479731205000},"page":"889-903","source":"Crossref","is-referenced-by-count":13,"title":["Aminoalkyl Derivatives of 8\u2010Alkoxypurine\u20102,6\u2010diones: Multifunctional 5\u2010HT<sub>1A<\/sub>\/5\u2010HT<sub>7<\/sub> Receptor Ligands and PDE Inhibitors with Antidepressant Activity"],"prefix":"10.1002","volume":"349","author":[{"given":"Gra\u017cyna","family":"Ch\u0142o\u0144\u2010Rzepa","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry Jagiellonian University Medical College Krak\u00f3w Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agnieszka","family":"Zag\u00f3rska","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry Jagiellonian University Medical College Krak\u00f3w Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pawe\u0142","family":"\u017bmudzki","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry Jagiellonian University Medical College Krak\u00f3w Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam","family":"Bucki","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry Jagiellonian University Medical College Krak\u00f3w Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcin","family":"Ko\u0142aczkowski","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry Jagiellonian University Medical College Krak\u00f3w Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Partyka","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy Jagiellonian University Medical College Krak\u00f3w Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Weso\u0142owska","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy Jagiellonian University Medical College Krak\u00f3w Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Grzegorz","family":"Kazek","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Screening Jagiellonian University Medical College Krak\u00f3w Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monika","family":"G\u0142uch\u2010Lutwin","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Screening Jagiellonian University Medical College Krak\u00f3w Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agata","family":"Siwek","sequence":"additional","affiliation":[{"name":"Department of Pharmacobiology Jagiellonian University Medical College Krak\u00f3w Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriela","family":"Starowicz","sequence":"additional","affiliation":[{"name":"Department of Pharmacobiology Jagiellonian University Medical College Krak\u00f3w Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maciej","family":"Paw\u0142owski","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry Jagiellonian University Medical College Krak\u00f3w Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2016,11,21]]},"reference":[{"key":"e_1_2_6_2_1","unstructured":"WHO (World Health Organization) Resolution WHA 65:4: The global burden of mental disorders and the need for a comprehensive coordinated response from health and social sectors at the country level. 65thWorld Health Assembly 2012 Geneva Switzerland."},{"key":"e_1_2_6_3_1","unstructured":"WHO (World Health Organization) International Classification of Diseases and Related Health Problems 10thRevision1992 Geneva Switzerland."},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.289.23.3095"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1001\/archpsyc.64.3.327"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-010-2097-z"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm991151j"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm049743b"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2011.12.039"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2010.03.019"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2015.00162"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40263-015-0236-0"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2014.00250"},{"key":"e_1_2_6_14_1","first-page":"65","volume":"9","author":"Costa L.","year":"2015","journal-title":"Frontiers Behav. 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