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-HT4 serotonin receptor, coupled to the G protein Gs, plays important physiological and pathophysiological roles in the heart, urinary bladder, gastrointestinal tract and the adrenal gland. Both 5-HT4 antagonists and agonists have been developed in the aim to treat diseases in these organs. 5-HT4 agonists might have beneficial effects in the central nervous system (CNS) and therefore, 5-HT4 antagonists might cause CNS side effects. In this study, we have developed new amphoteric 5-HT4 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-HT4 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 (Log D-Oct7.4) was tested for some of the synthesized ligands. The main structure-affinity characteristics of the 5-HT4 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-HT4 receptor. These new molecules may be useful to target peripheral 5-HT4 receptors. (C) 2010 Elsevier Ltd. All rights reserved.