N 1-arylsulfonyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives are potent and selective 5-HT 6 receptor antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 15, Issue 2, 2005, Pages 379-383

  Cole, Derek C ^a   Ellingboe, John W ^a   Lennox, William J ^a   Mazandarani, Hossein ^b   Smith, Deborah L ^b   Stock, Joseph R ^a   Zhang, Guoming ^b   Zhou, Ping ^b   Schechter, Lee E ^b  

^a WYETH RESEARCH   (United States)

^b PFIZER INC   (United States)

Author keywords

5 HT 6 antagonists; 5 Hydroxytryptamine 6 antagonists

Indexed keywords

4 [3 (1,2,3,6 TETRAHYDROPYRIDIN 4 YL) 1H INDOLE 1 SULFONYL]PHENYLAMINE; 4 [3 (1,2,3,6 TETRAHYDROPYRIDIN 4 YL) 5 METHOXY 1H INDOLE 1 SULFONYL]PHENYLAMINE; ADENYLATE CYCLASE; INDOLE DERIVATIVE; SEROTONIN 6 RECEPTOR; SEROTONIN ANTAGONIST; UNCLASSIFIED DRUG; SEROTONIN RECEPTOR;

ANIMAL CELL; ARTICLE; BINDING AFFINITY; CONTROLLED STUDY; DRUG RECEPTOR BINDING; DRUG SYNTHESIS; ENZYME SYNTHESIS; HUMAN; HUMAN CELL; NONHUMAN; HELA CELL; METABOLISM; STRUCTURE ACTIVITY RELATION; SYNTHESIS;

ADENYLATE CYCLASE; HELA CELLS; HUMANS; INDOLES; RECEPTORS, SEROTONIN; SEROTONIN ANTAGONISTS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 10644294547     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2004.10.064     Document Type: Article

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18. 6 membrane preparation: cultured HeLa cells expressing h5-HT6 receptors are harvested and centrifuged at low speed (1000 × g) for 5 min to remove the culture media. The harvested cells are suspended in 1 volume of fresh physiological phosphate buffered saline (PBS) solution and recentrifuged at the same speed. This operation is repeated once more. The collected cells are then homogenized in 10 volumes of 50 mM Tris-HCl, pH 7.4 and 0.5 mM EDTA. The homogenate is centrifuged at 900 × g for 10 min and the supernatant collected. The supernatant is then centrifuged at 40,000 × g for 30 min. The pellet is resuspended in 10 volumes of Tris-HCl buffer and recentrifuged at the same speed. The final pellet is suspended in a small volume of Tris-HCl buffer and the tissue protein content is determined in aliquots of 10-25 μL volumes. The volume of the suspended cell membranes is adjusted to give a tissue protein concentration of 1.0 mg/mL of suspension. The prepared membrane suspension (10 times concentrated) is aliquoted in 1.0 mL volumes and stored at -70°C until used in subsequent binding experiments
19. 3H]-LSD, 100 μL membrane protein (20-50 μg protein). Incubate at room temperature for 2 h and harvest reaction mixture by using Packard 96 well harvest system followed by counting the plate in Top Count machine (Packard)
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22. -10 M for 10 min at 37°C (antagonist assay require a second incubation with the addition of 100 nM 5HT). The assay is terminated by the addition of 0.5 M percloric acid. Intracellular cAMP levels were determined by radioimmunoassay through the cAMP SPA screening kit. Data were analyzed graphically with GraphPad Prism (GraphPad Software, San Diego, CA)