title: Development of high-affinity 5-HT3 receptor antagonists. Structure-affinity relationships of novel 1,7-annelated indole derivatives.
abstract: 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-pyri do [3,2,1-jk]carbazol-11-one hydrochloride (24b) (INN cilansetron) shows that the compound displays, besides a high affinity for 5-HT3 receptors (Ki = 0.19 nM), a weak affinity for sigma-receptors (Ki = 340 nM), muscarine M1 receptors (Ki = 910 nM), and 5-HT4 receptors (Ki = 960 nM) and no affinity (Ki > or = 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.
authors.affiliation: Solvay Duphar B.V., Section Drug Discovery, Weesp, The Netherlands.
authors.forename: I
authors.initials: I
authors.lastname: van Wijngaarden
authors.forename: D
authors.initials: D
authors.lastname: Hamminga
authors.forename: R
authors.initials: R
authors.lastname: van Hes
authors.forename: P J
authors.initials: PJ
authors.lastname: Standaar
authors.forename: J
authors.initials: J
authors.lastname: Tipker
authors.forename: M T
authors.initials: MT
authors.lastname: Tulp
authors.forename: F
authors.initials: F
authors.lastname: Mol
authors.forename: B
authors.initials: B
authors.lastname: Olivier
authors.forename: A
authors.initials: A
authors.lastname: de Jonge
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D007093:Imidazoles / Q000737:chemistry*; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D017294:Ondansetron / Q000737:chemistry*; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011985:Receptors, Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology
chemical_list: D002227:Carbazoles; D007093:Imidazoles; D007211:Indoles; D011725:Pyridines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C059068:GR 65630; C084473:cilansetron; D017294:Ondansetron