Non-imidazole histamine H3 Ligands. Part VII. Synthesis, in vitro and in vivo characterization of 5-substituted-2-thiazol-4-n-propylpiperazines

Roman Guryn, Marek Staszewski, Anna Stasiak, Daniel McNaught Flores, Wiesława Agnieszka Fogel, Rob Leurs, Krzysztof Walczynski*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review


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.

Original languageEnglish
Article number326
Pages (from-to)1-20
Number of pages20
Issue number2
Publication statusPublished - 3 Feb 2018


  • 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

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