Abstract
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’ brain in a manner and degree similar to the reference H3 antagonist Ciproxifan.
Highlights
The histamine H3 receptors were first identified in 1983 in the rat brain by J.-Ch
In continuation of our search for new highly active and selective non-imidazole histamine H3 receptor antagonists, the first step of this study aimed to clarify the significant difference between the potencies of the 4-hydroxypiperidine derivatives and their 3-(methylamino)propyloxy analogues, bearing ω-(benzofuran-2-yl)alkyl and ω-phenylakyl moieties, respectively
The highest in vitro potency as an H3 receptor antagonist for both series was observed for themethyl derivative of 4-hydroxypiperidine 1a (ADS-003) and the benzyl derivative of 3-(methylamino)propan-1-ol 2d
Summary
The histamine H3 receptors were first identified in 1983 in the rat brain by J.-Ch. Schwartz and coworkers [1]. The presence of H3 receptors was confirmed in the human brain a few years later [2]. H3-antagonists/inverse agonists have been proposed for the treatment of cognitive disorders, such as attention-deficit hyperactivity disorder (ADHD) [12] and Alzheimer’s disease [13] as well as of memory and learning deficits [10]. They may be useful in epilepsy [14], schizophrenia [15], and obesity [16]
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