Pain is a very unpleasant experience that makes life extremely uncomfortable. The histamine H4receptor (H4R) is a promising target for the treatment of inflammatory and immune diseases, as well as pain. H4R ligands have demonstrated analgesic effects in a variety of pain models, including inflammatory pain. Continuing the search for active H4R ligands among the alkyl derivatives of 1,3,5-triazine, we obtained 19 new compounds in two series: acyclic (I) and aliphatic (II). In vitro pharmacological evaluation showed their variable affinity for H4R. The majority of compounds showed a moderate affinity for this receptor (Ki> 100 nM), while all compounds tested in ß-arrestin and cAMP assays showed antagonistic activity. The most promising, compound6, (4-(cyclopentylmethyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine; Ki= 63 nM) was selected for further in vitro evaluation: blood-brain barrier permeability (PAMPA assay; Pe= 12.26 × 10−6cm/s) and toxicity tests (HepG2 and SH-5YSY cells; no toxicity up to 50 µM). Next, compound6tested in vivo in a carrageenan-induced inflammatory pain model showed anti-inflammatory and analgesic effects (strongest at 50 mg/kg i.p.). Furthermore, in a histamine- and chloroquine-induced pruritus model, compound6at a dose of 25 mg/kg i.p. and 50 mg/kg i.p., respectively, reduced the number of scratch bouts. Thus, compound6is a promising ligand for further studies.