Dual Target Ligands with 4-tert-Butylphenoxy Scaffold as Histamine H3 Receptor Antagonists and Monoamine Oxidase B Inhibitors

Abstract

Dual target ligands are a promising concept for the treatment of Parkinson’s disease (PD). A combination of monoamine oxidase B (MAO B) inhibition with histamine H₃ receptor (H₃R) antagonism could have positive effects on dopamine regulation. Thus, a series of twenty-seven 4-tert-butylphenoxyalkoxyamines were designed as potential dual-target ligands for PD based on the structure of 1-(3-(4-tert-butylphenoxy)propyl)piperidine (DL76). Probed modifications included the introduction of different cyclic amines and elongation of the alkyl chain. Synthesized compounds were investigated for human H₃R (hH₃R) affinity and human MAO B (hMAO B) inhibitory activity. Most compounds showed good hH₃R affinities with K_i values below 400 nM, and some of them showed potent inhibitory activity for hMAO B with IC₅₀ values below 50 nM. However, the most balanced activity against both biological targets showed DL76 (hH₃R: K_i = 38 nM and hMAO B: IC₅₀ = 48 nM). Thus, DL76 was chosen for further studies, revealing the nontoxic nature of DL76 in HEK293 and neuroblastoma SH-SY5Ycells. However, no neuroprotective effect was observed for DL76 in hydrogen peroxide-treated neuroblastoma SH-SY5Y cells. Furthermore, in vivo studies showed antiparkinsonian activity of DL76 in haloperidol-induced catalepsy (Cross Leg Position Test) at a dose of 50 mg/kg body weight.