Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder whose prevalence has an incidence in senior citizens. Unfortunately, current pharmacotherapy only offers symptom relief for patients with side effects such as bradycardia, nausea, and vomiting. Therefore, there is a present need to provide other therapeutic alternatives for treatments for these disorders. The 5-HT4 receptor is an attractive therapeutic target since it has a potential role in central and peripheral nervous system disorders such as AD, irritable bowel syndrome, and gastroparesis. Quantitative structure-activity relationship analysis of a series of 62 active compounds in the 5-HT4 receptor was carried out in the present work. The structure-activity relationship was estimated using three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques based on these structures’ field molecular (force and Gaussian field). The best force-field QSAR models achieve a value for the coefficient of determination of the training set of R2training = 0.821, and for the test set R2test = 0.667, while for Gaussian-field QSAR the training and the test were R2training = 0.898 and R2test = 0.695, respectively. The obtained results were validated using a coefficient of correlation of the leave-one-out cross-validation of Q2LOO = 0.804 and Q2LOO = 0.886 for force- and Gaussian-field QSAR, respectively. Based on these results, novel 5-HT4 partial agonists with potential biological activity (pEC50 8.209–9.417 for force-field QSAR and 9.111–9.856 for Gaussian-field QSAR) were designed. In addition, for the new analogues, their absorption, distribution, metabolism, excretion, and toxicity properties were also analyzed. The results show that these new derivatives also have reasonable pharmacokinetics and drug-like properties. Our findings suggest novel routes for the design and development of new 5-HT4 partial agonists.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder that mainly affects people over 60 years old
The 5-HT4 receptor (5-HT4 R) belongs to a superfamily of G-protein coupled receptors (GPCRs) [2,3,4]. This receptor is highly expressed in the brain regions of the hippocampus, amygdala, and cerebral cortex, areas of the brain related to short- and long-term memory and cognitive processing, so that deterioration of this region would be associated with neurological diseases such as Alzheimer’s disease [5,6]
The 5-HT4 R has been reported to play an essential role in disorders of the central nervous system (CNS) such as AD [7,8], peripheral nervous system (PNS) disorders [9], irritable bowel syndrome [10,11,12], and gastroparesis [13,14,15]
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder that mainly affects people over 60 years old. The current pharmacotherapy only provides palliative treatments, reducing the associated symptoms through the increase of cholinergic function This pharmacotherapy can produce unwanted side effects such as abdominal pain, muscle cramps, tremors, and fatigue, among others [1]. Nirogi et al reported a series of 5-HT4 R compounds with 3-isopropylimidazo [1,5-a]-pyridine-carboxamide scaffold, most of which showed cognition-enhancing properties in animal models [22]. Their absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties were not satisfactory due to their low ability to penetrate the blood-brain barrier. Nirogi reported new 5-HT4 R partial agonists with good
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