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

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 -methyl--3-phenylalkyl-2-[2-(4-n-propylpiperazin-1-yl)-1,3-thiazol-5-yl]ethan-1-amine () exhibits high in vitro potency toward H₃ guinea pig jejunal receptors, with pA₂ = 8.27. To optimize the structure of the lead compound , a series of 5-substituted-2-thiazol-4--propylpiperazines were synthesized and subjected to in vitro pharmacological characterization; the alkyl chain between position 2 of the thiazole ring and the terminal secondary -methylamino function was elongated from three to four methylene groups and the -methylamino functionality was substituted by benzyl-, 2-phenylethyl-, and 3-phenyl-propyl- moieties. SAR studies on novel non-imidazole, 5-substituted-2-thiazol-4--propyl-piperazines showed that the most active compound (pA₂ = 8.38), additionally possessed a weak competitive H₁-antagonistic activity. Therefore, compound , 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). exhibited nanomolar affinity for both rH₃R and hH₃R receptors. It was also shown that, 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.