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Non-Imidazole Histamine H3 Ligands. Part VII. Synthesis, In Vitro and In Vivo Characterization of 5-Substituted-2-thiazol-4-n-propylpiperazines

Department of Synthesis and Technology of Drugs, Medical University of Lodz, ul. Muszyńskiego 1, 90-145 Łódź, Poland
Department of Hormone Biochemistry, Medical University of Lodz, ul. Żeligowskiego 7/9, 90-752 Łódź, Poland
Amsterdam Institute of Molecules, Medicines & Systems, Division of Medicinal Chemistry, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands
Author to whom correspondence should be addressed.
Molecules 2018, 23(2), 326;
Received: 18 January 2018 / Revised: 31 January 2018 / Accepted: 1 February 2018 / Published: 3 February 2018
(This article belongs to the Special Issue Focusing on Sulfur in Medicinal Chemistry)
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. View Full-Text
Keywords: histamine H3 receptor non-imidazole antagonists; N-methyl-N-ω-phenylalkyl-ω-[2-(4-n-propylpiperazin-1-yl)-1,3-thiazol-5-yl]alkan-1-amines histamine H3 receptor non-imidazole antagonists; N-methyl-N-ω-phenylalkyl-ω-[2-(4-n-propylpiperazin-1-yl)-1,3-thiazol-5-yl]alkan-1-amines
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MDPI and ACS Style

Guryn, R.; Staszewski, M.; Stasiak, A.; McNaught Flores, D.; Fogel, W.A.; Leurs, R.; Walczyński, K. Non-Imidazole Histamine H3 Ligands. Part VII. Synthesis, In Vitro and In Vivo Characterization of 5-Substituted-2-thiazol-4-n-propylpiperazines. Molecules 2018, 23, 326.

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