Abstract
H3 receptors present on histaminergic and non-histaminergic neurons, act as autoreceptors or heteroreceptors controlling neurotransmitter release and synthesis. Previous, studies have found that the compound N-methyl-N-3-phenylalkyl-2-[2-(4-n-propylpiperazin-1-yl)-1,3-thiazol-5-yl]ethan-1-amine (ADS-531, 2c) exhibits high in vitro potency toward H3 guinea pig jejunal receptors, with pA2 = 8.27. To optimize the structure of the lead compound ADS-531, a series of 5-substituted-2-thiazol-4-n-propylpiperazines 3 were synthesized and subjected to in vitro pharmacological characterization; the alkyl chain between position 2 of the thiazole ring and the terminal secondary N-methylamino function was elongated from three to four methylene groups and the N-methylamino functionality was substituted by benzyl-, 2-phenylethyl-, and 3-phenyl-propyl- moieties. SAR studies on novel non-imidazole, 5-substituted-2-thiazol-4-n-propyl-piperazines 3 showed that the most active compound 3a (pA2 = 8.38), additionally possessed a weak competitive H1-antagonistic activity. Therefore, compound ADS-531, which did not exhibit any H1-antagonistic activity, was chosen for further evaluation for its affinity to the recombinant rat and human histamine H3 receptors (rH3R and hH3R, respectively). ADS-531 exhibited nanomolar affinity for both rH3R and hH3R receptors. It was also shown that, ADS-531 given subchronically to rats (s.c. 3 mg/kg, 5 days) penetrated the brain, where it affected dopamine, noradrenaline and serotonin concentration; however, it did not affect histamine concentration nor feeding behavior.
Highlights
The H3 receptors mediate the diverse biological effects of the neurotransmitter histamine [1] and they are widely expressed in the mammalian brain, in areas involved in cognitive processes and arousal, i.e., the cerebral cortex, hippocampus, basal ganglia, and hypothalamus [2,3]
The apparent lack of the effects of the tested compound on the histaminergic system was by no means caused by the lack of its ability to cross the blood-brain barrier
Higher affinity was observed for ADS-531 at the human H3 R than thioperamide and pKi of histamine (7.7 ± 0.1)
Summary
The H3 receptors mediate the diverse biological effects of the neurotransmitter histamine [1] and they are widely expressed in the mammalian brain, in areas involved in cognitive processes and arousal, i.e., the cerebral cortex, hippocampus, basal ganglia, and hypothalamus [2,3]. H3 receptors are located on histaminergic or non-histaminergic neurons, respectively acting as autoreceptors or heteroreceptors, controlling the release and synthesis of histamine [4] and of multiple neurotransmitters such as acetylcholine [5], norepinephrine [6] and dopamine [7] These data suggested that H3 antagonists could affect a number of behaviors and be useful in the treatment of cognitive deficits. Molecules 2018, 23, 326 multiple neurotransmitters such as acetylcholine [5], norepinephrine [6] and dopamine [7] These data suggested that H3 antagonists could affect a number of behaviors and be useful in the treatment associated withdeficits a variety of disease including. [8], attention deficit hyperactivity disorder (ADHD) [9], schizophrenia [10], and obesity [11].
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