Novel 5-HT7 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-HT7 receptor. Effects on basal adenylate cyclase activity were measured using HEK-293 cells expressing the rat 5-HT7. 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 (R2 = 0.97, SE = 0.18). Docking of inverse agonists at the binding site of a model of the helical parts of the 5-HT7 receptor, based on the alpha carbon template for 7-TM GPCRs, revealed interesting molecular interactions and a possible explanation for observed structure-activity relationships.
Department of Medicinal Chemistry, Center for Pharmacy, State University of Groningen, A. Deusinglaan 1, NL-9713 AV Groningen, The Netherlands. e.s.vermeulen@farm.rug.nl
Erik S
ES
Vermeulen
Marjan
M
van Smeden
Anne W
AW
Schmidt
Jeffrey S
JS
Sprouse
Håkan V
HV
Wikström
Cor J
CJ
Grol
D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D051381:Rats; D011985:Receptors, Serotonin / Q000737:chemistry / Q000187:drug effects; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000067956:Adenylyl Cyclase Inhibitors; D007546:Isoquinolines; D008024:Ligands; D010879:Piperazines; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D013449:Sulfonamides; C104425:serotonin 7 receptor