Serotonin (5-HT) is a naturally occurring excitatory neurotransmitter in the CNS and a locally acting vasoactive signalling molecule with diverse effects in the human cardiovascular system. 5-HT is suggested to be involved in the pathophysiological progression of heart failure (HF), due to previous studies indicating increased expression of 5-HT4 receptors in the left ventricle of failing hearts in both humans and animal models. In the human heart, stimulation of 5-HT4 receptors activates adenylyl cyclase (AC) and increases cAMP levels, thus activating a similar signalling pathway as the β-adrenoceptors, producing enhanced rate (chronotropic effect), force of contraction (inotropic effect) and hastening of contraction-relaxation cycle (lusitropic effect). New treatment of HF and atrial fibrillation with 5-HT4 receptor antagonists has been suggested to be beneficial by recent studies. However, further development of 5-HT4 receptor ligands will require further studies of efficacy, as well as elimination of the potential harmful risk of hERG potassium channel binding causing QT prolongation with increased risk of ventricular arrhythmia (TdP).
With the aim of developing new 5-HT4 antagonists for further drug development, we have synthesised 19 novel acidic N-aryl sulfonamides based on three aromatic ring systems: Indole-3-carboxylic acid sulfonamides 5-8, 1,4-benzodioxane-5-carboxylic acid sulfonamides 13-19, and 3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxylic acid (piboserod) sulfonamides 26-33. The new N-aryl sulfonamides were characterized by 1H/13C-NMR spectroscopy, HPLC analysis and the logarithmic distribution between phosphate buffer with pH 7.4 and n-octanol (log Doct7.4). The compounds were also pharmacologically evaluated to determine h5-HT4(b) receptor binding affinity, in a [3H]GR113808 radioligand binding assay, and antagonist property, in an adenylyl cyclase assay. The reference compounds used were GR113808 and SB207266 (Piboserod®). The structure-affinity relationships were evaluated based on the various side-chain substituents introduced to the N-aryl sulfonamides.
The piboserod sulfonamides and the benzodioxan sulfonamides seem to have higher affinity for the 5-HT4 receptor compared to the indole sulfonamides. The replacement of the hydrogen bond donor NH- in the indole ring by a hydrogen bond acceptor oxygen in the oxazino[3,2-a] ring of piboserod and in the benzodioxan ring, could be favourable for obtaining increased affinity for the 5-HT4 receptor, as indicated in earlier studies. Incorporating various side-chain groups to the piboserod and benzodioxan derivatives seem to alter the affinity for the 5-HT4 receptor, but increasing the side-chain length could not reveal any significant changes to the affinity. Electron withdrawing or electron donating side-chain groups seem to reduce the affinity for the receptor, compared to other substituents. More studies should be initiated to reveal any influence on the hydrophobic pocket and to the affinity for the 5-HT4 receptor, by using various substituents on N-aryl sulphonamides. Future studies should examine the hERG potassium channel affinity of the novel acidic N-aryl sulphonamides as well, since this will be critical for further clinical development.