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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.

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