A number of benzoates derived from 4-amino-5-chloro-2-methoxybenzoic acid and substituted 1-piperidineethanol were synthesized and found to be potent 5-HT4 receptor agonists in the electrically-stimulated myenteric plexus and longitudinal muscle of the guinea pig ileum and the rat esophagus muscle. Monosubstitution of the piperidine ring with Me, OH, NH-Ac, or CONH2 groups gave compounds equipotent to 7a (ML 10302), a 5-HT4 receptor agonist previously reported to have nanomolar affinity. 7a,k were as potent as serotonin (5-HT) but had maximal responses which were only 60-80% of that of 5-HT, suggesting a partial agonist profile for these compounds. Binding assays were performed with [3H]GR 113808 in the rat striatum, and several of these compounds were found to have nanomolar affinity for 5-HT4 receptors (7a, Ki = 1.07 +/- 0.5 nM; 7k, Ki = 1.0 +/- 0.3 nM). The introduction of two methyl groups on the piperidine ring brought about a dramatic change in the pharmacological profile of 2-[(cis- and trans-3,5-dimethylpiperidinyl)ethyl]-4-amino-5-chloro-2- methoxybenzoate, 7g,h. 7g (Ki = 0.26 +/- 0.06 nM) inhibited the relaxant action of 5-HT in the rat esophagus muscle with a pA2 value of 8.6. The advantage of the ester function was demonstrated by comparing the activity of several such compounds at 5-HT4 receptors with those of the corresponding amidic derivatives. This difference was less marked when the basic moiety was sterically constrained as in the quinuclidine and tropane moieties. Structural analyses of 7a,g were performed by determining their X-ray crystal structures and by molecular modeling (SYBYL). A relatively limited number of minimum energy conformers was found for both compounds. They were characterized by the cis folded conformation of the ethyl chain and by the orientation of the lone pair of the nitrogen atom pointing out of the molecule as seen in conformationally-constrained benzamides such as zacopride and renzapride. A hypothetical model for the 5-HT4 receptor with two sites for the binding of agonist and antagonist molecules was proposed.

How anti-Alzheimer's drug candidates that reduce amyloid 1-42 peptide fibrillization interact with the most neurotoxic species is far from being understood. We report herein the capacity of sugar-based peptidomimetics to inhibit both Aβ1-42 early oligomerization and fibrillization. A wide range of bio- and physicochemical techniques, such as a new capillary electrophoresis method, nuclear magnetic resonance, and surface plasmon resonance, were used to identify how these new molecules can delay the aggregation of Aβ1-42. We demonstrate that these molecules interact with soluble oligomers in order to maintain the presence of nontoxic monomers and to prevent fibrillization. These compounds totally suppress the toxicity of Aβ1-42 toward SH-SY5Y neuroblastoma cells, even at substoichiometric concentrations. Furthermore, demonstration that the best molecule combines hydrophobic moieties, hydrogen bond donors and acceptors, ammonium groups, and a hydrophilic β-sheet breaker element provides valuable insight for the future structure-based design of inhibitors of Aβ1-42 aggregation.