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.
Benzoxazepines constitute a huge number of organic compounds widely described in the literature. Many of them are distinguished by their biological properties.Among them, our attention was drawn to 1,5-benzoxazepine derivatives due to their interesting pharmacological properties. As is reported in the literature, these compounds are not only good building blocks in organic synthesis but also have interesting biological and pharmacological properties. This article is the first review publication to describe the synthesis methods and unique properties of 1,5-benzoxazepines. Literature reports widely describe the biological properties of 1,5-benzoxazepine, like anticancer, antibacterial, or antifungal activities.
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