Abstract
Presynaptic histamine H&sub3; receptors (H&sub3;R) 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 H&sub3;R antagonists, and there is a great interest for potent, brain-penetrating H&sub3; 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 H&sub3; receptor (jejunum), with pA&sub2; = 8.47 and 7.79, respectively (the reference compound used was thioperamide with pA&sub2; = 8.67). Furthermore, following the replacement of 4-hydroxypiperidine with a 3-(methylamino)propyloxy chain, the pA&sub2; 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 H&sub3; receptor antagonists/inverse agonists, i.e., ADS-003, was evaluated for its affinity to the recombinant rat and human histamine H&sub3; 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’ brain in a manner and degree similar to the reference H&sub3; antagonist Ciproxifan.