![]() ![]() Citation 15 Moreover, the inhibition of AChE may not only result in increased levels of ACh but may also affect the Aβ aggregation. Citation 2, Citation 11Īcetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are enzymes responsible for the hydrolysis of acetylcholine and the increase in their activity leads to cognitive disorders. Accordingly, the development of multitarget compounds including H 3 receptor-blocking properties has been of great interest. Citation 14 These classes may have synergistic effect leading to the increase of their therapeutic efficacy in the treatment of disorders related to neurotransmitter deficits, such as AD. New classes of H 3R antagonists with additional pharmacological properties have been described. Citation 13 In the early stage of its discovery, pitolisant showed selectivity towards H 3R and induced central histaminergic transmissions in animal models increasing wakefulness and resulted in increased release of dopamine and ACh in the prefrontal cortex of rats. Citation 12 Pitolisant, is the first H 3R antagonist/inverse agonist which received the approval in Europe and United States for the treatment of narcolepsy with or without cataplexy. Citation 11 Thus the precognitive use of H 3R antagonists/inverse agonists for the treatment of CNS-related disorders, such as depression, schizophrenia, PD, and AD is being investigated. Besides its inhibitory activity as an autoreceptor, modulating the release of other neurotransmitters such as noradrenaline, serotonin, dopamine and acetylcholine has been observed by H 3 hetero receptor located on non-histaminergic neurons. H 3R was first identified on presynaptic histaminergic neurons acting as autoreceptors. Histamine H 3 receptors (H 3Rs) belong to the family of G protein-coupled receptors (GPCR). The combination of H 3R antagonist pharmacophore and acetylcholinesterase pharmacophore is one of the most interesting and promising combinations among MTDLs for the treatment of AD. Among these targets, neurotransmitters such as ACh, histamine, dopamine and glutamate play major roles in the progressive deterioration of cognitive functions. Citation 8 The pathogenesis of most neurodegenerative diseases (especially AD) is linked to different pharmacological targets. Citation 6, Citation 7 MTDLs are compounds that affect more than one pathophysiological pathway since they can be rationally designed as structures with pharmacophore moieties that bind to different receptors and enzymes. MTDLs are synthesised mainly as potential therapeutics for the treatment of multifactorial diseases such as neurodegenerative diseases. Citation 4, Citation 5 Therefore, the new pharmacological approach is to design single molecules that modulate multiple targets simultaneously, so-called multitarget-directed ligands (MTDLs). Owing to the complex pathology of the disease, a single ligand for a certain target is not sufficient to produce a relevant therapeutic effect. Citation 3 The drugs approved for treating AD only offer a symptomatic treatment, but fail to stop the neurodegenerative process. Citation 1, Citation 2 The histopathological changes observed in AD patients include deficiency in cholinergic neurotransmission, accumulation of amyloid-β (Aβ) peptide in the form of amyloid plaques in the brain, intracellular neurofibrillary tangles and progression of inflammation and damage caused by oxidative stress. ![]() These findings suggest that compound 3s can be a lead structure for developing new multi-targeting anti-AD agents.ĪD is a progressive irreversible neurodegenerative brain disorder and it is the most common form of dementia. The multitargeting potential of these H 3R ligands towards AChE, BuChE and MAO-B enzymes was evaluated to yield compound 3s (pyrrolidin-1-yl-(6-((5-(pyrrolidin-1-yl)pentyl)oxy)benzothiazol-2-yl)methanone) as the most promising MTDL with a K i value of 0.036 μM at H 3R and IC 50 values of 6.7 µM, 2.35 µM, and 1.6 µM towards AChE, BuChE, and MAO-B, respectively. The most affine compound, the 3-(azepan-1-yl)propyloxy-linked benzothiazole derivative 4b, displayed a K i value of 0.012 μM. Herein, we describe new benzothiazole-based derivatives as a privileged scaffold for histamine H 3 receptor ligands (H 3R). Therefore, it is assumed that multitargeted-directed ligands (MTDLs) which interact with different biological targets relevant to the diseases, might offer an improved therapeutic alternative than using the traditional “one-target, one-molecule” approach. Neurodegenerative diseases such as Alzheimer’s disease (AD) are multifactorial with several different pathologic mechanisms. ![]()
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