Development of high-affinity 5-HT3 receptor antagonists. Structure- affinity relationships of novel 1,7-annelated indole derivatives. 1

Article abstract of DOI:10.1021/jm00075a026

On the basis of the structures of ondansetron and GR 65,630, its ring- opened C-linked methylimidazole analogue, novel 1,7-annelated indole derivatives were synthesized as potential 5-HT₃ antagonists. Receptor binding studies show that all compounds display a high affinity for the 5- HT₃ receptors. In both series annelation results in compounds being 7 and 4 times more potent than the references ondansetron and GR 65,630, respectively. Similar to ondansetron, the 1,7-annelated indoles show little stereoselectivity. The (-)-isomers are only slightly more potent than the (+)-isomers. The receptor binding profile of l-10-[(2-methyl-1H-imidazol-1- yl)methyl]-5,6,8,9,10,11-hexahydro-4H-pyrido[3,2,1-jk]carbazol-11-one hydrochloride (24b) (INN cilansetron) shows that the compound displays, besides a high affinity for 5-HT₃ receptors (K(i) = 0.19 nM), a weak affinity for σ-receptors (K(i) = 340 nM), muscarine M₁ receptors (K(i) = 910 nM), and 5-HT₄ receptors (K(i) = 960 nM) and no affinity (K(i) ≥ 5000 nM) for all the other receptor types tested (n = 37). The new compounds fit the proposed necessary chemical template for binding: a heteroaromatic ring system, a coplanar carbonyl group, and a nitrogen center at well-defined distances. The enhanced potency of the annelated 1,7-indole derivatives indicates that the extra ring provides a favorable hydrophobic area for interaction with the 5-HT₃ receptor site. In vivo cilansetron is more potent and induces less central side effects than ondansetron. At present cilansetron is in clinical trials.