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.

Non-Imidazole Histamine H3 Ligands. Part VI. Synthesis and Preliminary Pharmacological Investigation of Thiazole-Type Histamine H3-Receptor Antagonists with Lacking a Nitrogen Nucleus in the Side Chain.

Background: Antagonists to the H3 receptor are considered to be potential drugs for the treatment of Alzheimer's disease, attention deficit-hyperactive disorder, memory and learning deficits, and epilepsy. The initial development of potent H3 receptor antagonists focused on extensive modification of the natural ligand histamine. However, it has appeared that imidazole-containing ligands are associated with inhibition of cytochrome P450 enzymes, caused by imidazole nitrogen complexation to heme iron in the active site of the enzyme.

Non-imidazole histamine H ligands: part V. synthesis and preliminary pharmacological investigation of 1-[2-thiazol-4-yl- and 1-[2-thiazol-5-yl-(2-aminoethyl)]-4--propylpiperazine derivatives.

Series of 1-[2-thiazol-4-yl-(2-aminoethyl)]- and 1-[2-thiazol-5-yl-(2-aminoethyl)]-4--propylpiperazine derivatives have been prepared and in vitro tested as H-receptor antagonists (the electrically evoked contraction of the guinea-pig jejunum). It appeared that by comparison of homologous pairs, the 1-[2-thiazol-5-yl-(2-aminoethyl)]-4--propylpiperazines (, and -) have much higher potency than their analogous 1-[2-thiazol-4-yl-(2-aminoethyl)]-4--propylpiperazines (-). Based on the obtained results, we observed the 5-position of 2-methyl-2-R-aminoethyl substituents in the thiazole ring is favourable for histamine H receptor antagonist activity, whereas its presence in position 4 leads, almost in each case, to strong decrease of activity.