{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,19]],"date-time":"2025-10-19T06:06:50Z","timestamp":1760854010409,"version":"build-2065373602"},"reference-count":46,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2018,2,3]],"date-time":"2018-02-03T00:00:00Z","timestamp":1517616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"departmental source of the Medical University of Lodz","award":["503\/3-016-01\/503-31-001","503\/5-087-02\/503-01"],"award-info":[{"award-number":["503\/3-016-01\/503-31-001","503\/5-087-02\/503-01"]}]},{"name":"COST Action","award":["CA 15135"],"award-info":[{"award-number":["CA 15135"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>H3 receptors present on histaminergic and non-histaminergic neurons, act as autoreceptors or heteroreceptors controlling neurotransmitter release and synthesis. Previous, studies have found that the compound N-methyl-N-3-phenylalkyl-2-[2-(4-n-propylpiperazin-1-yl)-1,3-thiazol-5-yl]ethan-1-amine (ADS-531, 2c) exhibits high in vitro potency toward H3 guinea pig jejunal receptors, with pA2 = 8.27. To optimize the structure of the lead compound ADS-531, a series of 5-substituted-2-thiazol-4-n-propylpiperazines 3 were synthesized and subjected to in vitro pharmacological characterization; the alkyl chain between position 2 of the thiazole ring and the terminal secondary N-methylamino function was elongated from three to four methylene groups and the N-methylamino functionality was substituted by benzyl-, 2-phenylethyl-, and 3-phenyl-propyl- moieties. SAR studies on novel non-imidazole, 5-substituted-2-thiazol-4-n-propyl-piperazines 3 showed that the most active compound 3a (pA2 = 8.38), additionally possessed a weak competitive H1-antagonistic activity. Therefore, compound ADS-531, which did not exhibit any H1-antagonistic activity, was chosen for further evaluation for its affinity to the recombinant rat and human histamine H3 receptors (rH3R and hH3R, respectively). ADS-531 exhibited nanomolar affinity for both rH3R and hH3R receptors. It was also shown that, ADS-531 given subchronically to rats (s.c. 3 mg\/kg, 5 days) penetrated the brain, where it affected dopamine, noradrenaline and serotonin concentration; however, it did not affect histamine concentration nor feeding behavior.<\/jats:p>","DOI":"10.3390\/molecules23020326","type":"journal-article","created":{"date-parts":[[2018,2,5]],"date-time":"2018-02-05T04:29:42Z","timestamp":1517804982000},"page":"326","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Non-Imidazole Histamine H3 Ligands. Part VII. Synthesis, In Vitro and In Vivo Characterization of 5-Substituted-2-thiazol-4-n-propylpiperazines"],"prefix":"10.3390","volume":"23","author":[{"given":"Roman","family":"Guryn","sequence":"first","affiliation":[{"name":"Department of Synthesis and Technology of Drugs, Medical University of Lodz, ul. Muszy\u0144skiego 1, 90-145 \u0141\u00f3d\u017a, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marek","family":"Staszewski","sequence":"additional","affiliation":[{"name":"Department of Synthesis and Technology of Drugs, Medical University of Lodz, ul. Muszy\u0144skiego 1, 90-145 \u0141\u00f3d\u017a, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Stasiak","sequence":"additional","affiliation":[{"name":"Department of Hormone Biochemistry, Medical University of Lodz, ul. \u017beligowskiego 7\/9, 90-752 \u0141\u00f3d\u017a, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"McNaught Flores","sequence":"additional","affiliation":[{"name":"Amsterdam Institute of Molecules, Medicines &amp; Systems, Division of Medicinal Chemistry, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wies\u0142awa","family":"Fogel","sequence":"additional","affiliation":[{"name":"Department of Hormone Biochemistry, Medical University of Lodz, ul. \u017beligowskiego 7\/9, 90-752 \u0141\u00f3d\u017a, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rob","family":"Leurs","sequence":"additional","affiliation":[{"name":"Amsterdam Institute of Molecules, Medicines &amp; Systems, Division of Medicinal Chemistry, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Krzysztof","family":"Walczy\u0144ski","sequence":"additional","affiliation":[{"name":"Department of Synthesis and Technology of Drugs, Medical University of Lodz, ul. Muszy\u0144skiego 1, 90-145 \u0141\u00f3d\u017a, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,2,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/S0301-0082(00)00039-3","article-title":"The physiology of brain histamine","volume":"63","author":"Brown","year":"2001","journal-title":"Prog. 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