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Presynaptic histamine H₃ receptors (H₃R) act as auto- or heteroreceptors controlling, respectively, the release of histamine and of other neurotransmitters in the central nervous system (CNS). The extracellular levels of several neurotransmitters are enhanced by H₃R antagonists, and there is a great interest for potent, brain-penetrating H₃ receptor antagonists/inverse agonists to compensate for the neurotransmitter deficits present in various neurological disorders. We have shown that 1-[(benzylfuran-2-yl)methyl]piperidinyl-4-oxyl- and benzyl- derivatives of N -propylpentan-1-amines exhibit high in vitro potencies toward the guinea pig H₃ receptor (jejunum), with pA₂ = 8.47 and 7.79, respectively (the reference compound used was thioperamide with pA₂ = 8.67). Furthermore, following the replacement of 4-hydroxypiperidine with a 3-(methylamino)propyloxy chain, the pA₂ value for the first group decreased, whereas it increased for the second group. Here, we present data on the impact of elongating the aliphatic chain between the nitrogen of 4-hydroxypiperidine or 3-(methylamino)propan-1-ol and the lipophilic residue. Additionally, the most active compound in this series of non-imidazole H₃ receptor antagonists/inverse agonists, i.e., ADS-003 , was evaluated for its affinity to the recombinant rat and human histamine H₃ receptors transiently expressed in HEK-293T cells. It was shown that ADS-003 , given parenterally for 5 days, reduced the food intake of rats, as well as changed histamine and noradrenaline concentrations in the rats&amp;rsquo; brain in a manner and degree similar to the reference H₃ antagonist Ciproxifan.

international journal of molecular sciences

4-Hydroxypiperidines and Their Flexible 3-(Amino)propyloxy Analogues as Non-Imidazole Histamine H3 Receptor Antagonist: Further Structure–Activity Relationship Exploration and In Vitro and In Vivo Pharmacological Evaluation