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Molecules 2018, 23(2), 326; https://doi.org/10.3390/molecules23020326

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

1
Department of Synthesis and Technology of Drugs, Medical University of Lodz, ul. Muszyńskiego 1, 90-145 Łódź, Poland
2
Department of Hormone Biochemistry, Medical University of Lodz, ul. Żeligowskiego 7/9, 90-752 Łódź, Poland
3
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.
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)
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Abstract

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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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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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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