The histamine H₃ receptor (H₃R) is a promising target in the development of new compounds for the treatment of mainly centrally occurring diseases. However, emerging novel therapeutic concepts have been introduced and some indications in the H₃R field, e.g. migraine, pain or allergic rhinitis, might take advantage of peripherally acting ligands. In this work, kojic acid-derived structural elements were inserted into a well established H₃R antagonist/inverse agonist scaffold to investigate the bioisosteric potential of γ-pyranones with respect to the different moieties of the H₃R pharmacophore. The most affine compounds showed receptor binding in the low nanomolar concentration range. Evaluation and comparison of kojic acid-containing ligands and their corresponding phenyl analogues (3—7) revealed that the newly integrated scaffold greatly influences chemical properties (S Log P, topological polar surface area (tPSA)) and hence, potentially modifies the pharmacokinetic profile of the different derivatives. Benzyl-1-(4-(3-(piperidin-1-yl)propoxy)phenyl)methanamine ligands 3 and 4 belong to the centrally acting diamine-based class of H₃R antagonist/inverse agonist, whereas kojic acid analogues 6 and 7 might act peripherally. The latter compounds state promising lead structures in the development of H₃R ligands with a modified profile of action.