5-HT4 Receptor Antagonists: Structure-Affinity Relationships and Ligand- Receptor Interactions

Abstract

Among serotonin receptors (5-HTRs), the 5-HT(4) subtype is of considerable interest because it is involved in (patho)physiological processes both in peripheral and central nervous systems. In addition to the clinical use of 5-HT(4R) agonists in the treatment of gastrointestinal motility disorders, the potential use of antagonists in the treatment of irritable bowel syndrome, arrhythmias and micturition disturbances are currently under investigation. This article will review the development of the most important classes of 5-HT(4R) antagonists with an emphasis on benzimidazole derivatives, their structure-affinity relationships, ligand-receptor interactions and pharmacological applications.

Pharmacophore Models for Metabotropic 5-HT Receptor Ligands

“…Among all the 5-HTRs, the most numerous pharmacophores have been constructed for 5-HT 3 R ligands, and these studies have been comprehensively reviewed by several authors [6][7][8][9][10]. In the case of agents acting at different subtypes of the remaining 5-HTRs, their pharmacophore models have not been so thoroughly and systematically reviewed, but only partly summarized -mainly in the papers describing ligands of individual 5-HTRs [11][12][13][14][15]. Fig.…”

“…In addition, the presence of ring B (representing, e.g., a pyrrole portion of indole) decreased ligand selectivity, whereas its absence could be compensated by substitutents at the protonated amine or at the aromatic ring A. Using X-ray crystallographic data and molecular mechanics calculations, Hacksell and co-workers investigated conformationally restricted 2-aminotetralins, characterized by different stereoselectivities (11)(12)(13) [24]. Taking into account several potential pharmacophore elements (a hydroxyl group, an aromatic ring, a nitrogen atom, its lone pair of electrons and a dummy atom (Du) mimicking the receptor carboxylate of an aspartic residue), they constructed different models, which were then tested by subsets of potent agonists, moderate agonists and inactive compounds.…”

5‐HT4 receptor agonists: similar but not the same

“…These compounds all have a bulky substitute of the basic nitrogen, most of them with the basic nitrogen included in a structured ring (Fig. 1), necessary to interact in a hydrophobic pocket of the receptor 77 . In contrast, the highly conserved Asp 100 is known to make an ionic bond with the protonated amine of 5‐HT derivatives.…”

Receptor regulatory properties evident in the molecular similarity of serotonin receptor ligands and purine nucleotides

“…The 5-HT 4 receptor antagonist model described by Lopez-Rodriguez et al (2002) highlights the similarity between 5-HT 3 and 5-HT 4 pharmacophores, and a difference in the acceptable substituent group volume on the basic N atom. A large substituent promotes selective binding at the 5-HT 4 receptor.…”