Novel 5-HT sub(7) Receptor Inverse Agonists. Synthesis and Molecular Modeling of Arylpiperazine- and 1,2,3,4-Tetrahydroisoquinoline-Based Arylsulfonamides

Novel 5-HT sub(7) Receptor Inverse Agonists. Synthesis and Molecular Modeling of Arylpiperazine- and 1,2,3,4-Tetrahydroisoquinoline-Based Arylsulfonamides

A series of arylpiperazine- and 1,2,3,4-tetrahydroisoquinoline-based arylsulfonamides was synthesized and evaluated for their interactions with the constitutively active 5-HT sub(7) receptor. Effects on basal adenylate cyclase activity were measured using HEK-293 cells expressing the rat 5-HT sub(7)...

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Veröffentlicht in:Journal of medicinal chemistry 2004-10, Vol.47 (22), p.5451-5466
Hauptverfasser: Vermeulen, E S, van Smeden, M, Schmidt, A W, Sprouse, J S, Wikstroem, H V, Grol, C J
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container_issue 22
container_start_page 5451
container_title Journal of medicinal chemistry
container_volume 47
creator Vermeulen, E S
van Smeden, M
Schmidt, A W
Sprouse, J S
Wikstroem, H V
Grol, C J
description A series of arylpiperazine- and 1,2,3,4-tetrahydroisoquinoline-based arylsulfonamides was synthesized and evaluated for their interactions with the constitutively active 5-HT sub(7) receptor. Effects on basal adenylate cyclase activity were measured using HEK-293 cells expressing the rat 5-HT sub(7). All ligands produced a decrease of adenylate cyclase activity, indicative of their inverse agonism. Additionally, computational studies with a set of 22 inverse agonists, including these novel inverse agonists and inverse agonists known from literature, resulted in a pharmacophore model and a CoMFA model (R super(2) = 0.97, SE = 0.18). Docking of inverse agonists at the binding site of a model of the helical parts of the 5-HT sub(7) receptor, based on the alpha carbon template for 7-TM GPCRs, revealed interesting molecular interactions and a possible explanation for observed structure-activity relationships.
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title Novel 5-HT sub(7) Receptor Inverse Agonists. Synthesis and Molecular Modeling of Arylpiperazine- and 1,2,3,4-Tetrahydroisoquinoline-Based Arylsulfonamides
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