This study focuses on the design, synthesis, molecular modeling and biological evaluation of a novel group of alkyl-1,3,5-triazinyl-methylpiperazines. New compounds were synthesized and their affinities for human histamine H<sub>4</sub> receptor (hH<sub>4</sub>R) were evaluated. Among them, 4-(cyclohexylmethyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (14) exhibited hH<sub>4</sub>R affinity with a K<sub>i</sub> of 160 nM and behaved as antagonist in functional assays: the cellular aequorin-based assay (IC<sub>50</sub> = 32 nM) and [<sup>35</sup>S]GTPγS binding assay (pK<sub>b</sub> = 6.67). In addition, antinociceptive activity of 14in vivo was observed in Formalin test (in mice) and in Carrageenan-induced acute inflammation test (in rats).