The synthesis and biological activity of 4-tert-pentylphenoxypropyl derivatives are described in this manuscript. All compounds (except one) showed human histamine H3 receptor affinity with Ki values below 760 nM. The inhibitory activity toward human monoamine oxidase B (hMAO B) was evaluated using a fluorometric Amplex-Red assay, and most of the compounds were effective in the submicromolar range. Among them, 1-(3-(4-tert-pPentylphenoxy)propyl)pyrrolidine (5) exhibited hMAO B inhibitory activity with an IC50 value of 4.5 nM. In addition, hMAO B inhibition by 5 was shown to be non-competitive and reversible. Further, recently described potent histamine H3 receptor ligands - 4-tert-pentylphenoxyalkyl derivatives (with a 4-8 carbon spacer) - were evaluated for hMAO B inhibitory activity, and some of them displayed activity in the submicromolar range. Selected compounds were also tested for human MAO A (hMAO A) inhibitory potencies and exhibited no activity. Moreover, molecular modeling studies were carried out for tested compounds to explain their molecular mechanism of hMAO B inhibition and the selectivity of compounds for hMAO B over hMAO A.
Keywords: 4-tert-Pentylphenoxy derivatives; Histamine H(3) receptor; Kinetic studies; Monoamine oxidase B; Small molecule inhibitors.
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