Design and synthesis of novel ligands for the 5-HT3 and the 5-HT4 receptor

Blum, Emily; Buchheit, Karl-Heinz; Buescher, H. H.; Gamse, R.; Kloeppner, E.; Meigel, H.; Papageorgiou, Christos; Waelchli, Rudolf; Révész, Láśzló

doi:10.1016/s0960-894x(00)80170-5

Cited by 12 publications

(3 citation statements)

References 14 publications

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“…SDZ-ICT 322 ( Fig. 1 ), is a competitive, highly potent 5-HT 3 receptor antagonist that contains key structural elements of both scopolamine and high affinity 5-HT 3 receptor antagonists such as granisetron and tropisetron ( Blum et al., 1992 ); it has the same tricyclic scopine moiety as scopolamine, which is rigidly linked to the flat heteroaromatic group (indole) found in granisetron and tropisetron. Docking of SDZ-ICT 322 into the 5-HT 3 receptor binding site predicted an orientation similar to granisetron and tropisetron, with its aromatic indole group close to the side chain of R92 from loop D and the scopine tricycle pointing towards the β-sheets of the principal face, surrounded by the aromatic rings of W90, W183 and Y234 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…1 ). The importance of this region is highlighted by SDZ-ICT 322, a ligand that is also a high affinity 5-HT 3 receptor antagonist (p A 2 = 10.6 in isolated rabbit vagus nerve, p K d = 9.2 in N1E cells) but has the same scopine tricyclic moiety as scopolamine directly linked to the aromatic indole ring ( Blum et al., 1992 ). This hypothesis is further supported by the low affinity of atropine which contains the same tetrahedral carbon, while the close analogue tropane benzoate, with a carbonyl linker, has high affinity at 5-HT 3 receptors (63 nM; Fozard, 1989 ).…”

Section: Discussionmentioning

confidence: 99%

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The muscarinic antagonists scopolamine and atropine are competitive antagonists at 5-HT 3 receptors

Lochner

Thompson

2016

Neuropharmacology

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Scopolamine is a high affinity muscarinic antagonist that is used for the prevention of post-operative nausea and vomiting. 5-HT3 receptor antagonists are used for the same purpose and are structurally related to scopolamine. To examine whether 5-HT3 receptors are affected by scopolamine we examined the effects of this drug on the electrophysiological and ligand binding properties of 5-HT3A receptors expressed in Xenopus oocytes and HEK293 cells, respectively. 5-HT3 receptor-responses were reversibly inhibited by scopolamine with an IC50 of 2.09 μM. Competitive antagonism was shown by Schild plot (pA2 = 5.02) and by competition with the 5-HT3 receptor antagonists [3H]granisetron (Ki = 6.76 μM) and G-FL (Ki = 4.90 μM). The related molecule, atropine, similarly inhibited 5-HT evoked responses in oocytes with an IC50 of 1.74 μM, and competed with G-FL with a Ki of 7.94 μM. The reverse experiment revealed that granisetron also competitively bound to muscarinic receptors (Ki = 6.5 μM). In behavioural studies scopolamine is used to block muscarinic receptors and induce a cognitive deficit, and centrally administered concentrations can exceed the IC50 values found here. It is therefore possible that 5-HT3 receptors are also inhibited. Studies that utilise higher concentrations of scopolamine should be mindful of these potential off-target effects.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The muscarinic antagonists scopolamine and atropine are competitive antagonists at 5-HT 3 receptors

Lochner

Thompson

2016

Neuropharmacology

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“…Of the quinoline class, one active molecule has been described thus far, Sandoz compound 9b. 15 Until recently, the indole-tropane derivative tropisetron (ICS-205 930) was the only antagonist at the 5-HT4 receptor, but its affinity (pA2 = 6.0-6.5) compared poorly with its preference for 5-HT3 receptors (PA, = 8.0-11.0;…”

Section: -Ht3mentioning

confidence: 99%