Understanding the Molecular Basis of 5-HT4 Receptor Partial Agonists through 3D-QSAR Studies.

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.

Discovery and pharmacological profile of new hydrophilic 5-HT(4) receptor antagonists.

The synthesis and pharmacological data of some new and potent hydrophilic 5-HT4 receptor antagonists are described. Propanediol derivative 25 was identified as a potent antagonist with low affinity for the hERG potassium channel and promising pharmacokinetics.

Design of fluorinated 5-HT(4)R antagonists: influence of the basicity and lipophilicity toward the 5-HT(4)R binding affinities.

Analogues of potent 5-HT(4)R antagonists possessing a fluorinated N-alkyl chain have been synthesized in order to investigate the effect of the resulting change in basicity and lipophilicity on the affinity and selectivity profile. We demonstrate that for this series, the affinity is decreased with decreased basicity of the piperidine's nitrogen atom. In contrast, the resulting increase in lipophilicity has minimal impact on binding affinity and selectivity. 3,3,3-Trifluoropropyl and 4,4,4-trifluorobutyl derivatives 6d and 6e have shown to bind to the 5-HT(4)R while maintaining their pharmacological profile and selectivity toward other 5-HT receptors.

Synthesis and pharmacological properties of novel hydrophilic 5-HT4 receptor antagonists.

Serotonin (5-hydroxytryptamine, 5-HT) is an important signalling molecule in the human body. The 5-HT(4) serotonin receptor, coupled to the G protein G(s), plays important physiological and pathophysiological roles in the heart, urinary bladder, gastrointestinal tract and the adrenal gland. Both 5-HT(4) antagonists and agonists have been developed in the aim to treat diseases in these organs. 5-HT(4) agonists might have beneficial effects in the central nervous system (CNS) and therefore, 5-HT(4) antagonists might cause CNS side effects. In this study, we have developed new amphoteric 5-HT(4) antagonists. A series of cyclic indole amide derivatives possessing an oxazine ring and a piperidine alkane carboxylic acid side chain and the corresponding prodrug esters were synthesized and their binding to 5-HT(4) receptors and antagonist properties were evaluated. In addition, an indole ester without the oxazine ring and the corresponding indole amide derivatives were also tested. Octanol-water distribution (LogD(Oct7.4)) was tested for some of the synthesized ligands. The main structure-affinity characteristics of the 5-HT(4) compounds tested were that the prodrug esters show higher affinity than their corresponding free acids, indole esters show higher affinity than the corresponding amides and ligands containing the oxazine ring in the indole skeleton show higher affinity than indole derivatives not containing the ring. One representative prodrug ester and its corresponding free acid were tested for binding on a panel of receptors and showed preserved selectivity for the 5-HT(4) receptor. These new molecules may be useful to target peripheral 5-HT(4) receptors.