title: Differential inverse agonist efficacies of SB-258719, SB-258741 and SB-269970 at human recombinant serotonin 5-HT7 receptors.
abstract: Recombinant 5-hydroxytryptamine 5-HT7 receptors are known to express constitutive, i.e., agonist-independent activity. Nonselective ligands, like methiothepin, ritanserin or clozapine behave as full inverse agonists at 5-HT7 receptors. The aim of the present study was to evaluate the degree of inverse agonist activity of three selective 5-HT7 receptor antagonists ((R)-3,N-dimethyl-N-[1-methyl-3-(4-methyl-piperidin-1-yl)propyl]benzene sulfonamide or SB-258719, R-(+)-1-(toluene-3-sulfonyl)-2-[2-(4-methylpiperidin-1-yl)ethyl]-pyrrolidine or SB-258741 and (R)-3-(2-(2-(4-methylpiperidin-1-yl)ethyl)-pyrrolidine-1-sulfonyl)-phenol or SB-269970) in the same model. cAMP accumulation was measured in intact Chinese hamster ovary (CHO) cells expressing human recombinant 5-HT7a receptors. In these cells, 5-HT stimulated cAMP levels and a series of ligands antagonized the effect of 5-HT with a 5-HT7 receptor-like profile. SB-258719 had no inverse agonist activity, SB-258741 behaved as a partial inverse agonist and SB-269970 was a quasi-full inverse agonist (as compared to methiothepin). The inverse agonist effect of SB-269970 was antagonized in a concentration-dependent manner by SB-258719. The widespread spectrum of inverse agonist activities shown by these compounds should help assessing the physiological relevance of constitutive 5-HT7 receptor activity in native tissues.
authors.affiliation: Neuroscience Research, Novartis Institutes for Biomedical Research, Novartis Pharma AG, WSJ-386.7.44, CH-4002 Basel, Switzerland.
authors.forename: Cécile
authors.initials: C
authors.lastname: Mahé
authors.forename: Erika
authors.initials: E
authors.lastname: Loetscher
authors.forename: Dominik
authors.initials: D
authors.lastname: Feuerbach
authors.forename: Werner
authors.initials: W
authors.lastname: Müller
authors.forename: Max P
authors.initials: MP
authors.lastname: Seiler
authors.forename: Philippe
authors.initials: P
authors.lastname: Schoeffter
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D003024:Clozapine / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004873:Ergolines / Q000494:pharmacology; D006801:Humans; D008152:Loxapine / Q000494:pharmacology; D008719:Methiothepin / Q000494:pharmacology; D010636:Phenols / Q000494:pharmacology; D010868:Pimozide / Q000494:pharmacology; D010869:Pindolol / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D010957:Plasmids / Q000235:genetics; D011759:Pyrrolidines / Q000494:pharmacology; D011869:Radioligand Assay; D011985:Receptors, Serotonin / Q000235:genetics / Q000378:metabolism*; D016713:Ritanserin / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology; D014105:Tosyl Compounds / Q000494:pharmacology; D014162:Transfection; D000096926:Benzenesulfonamides
chemical_list: D003024:Clozapine; D000242:Cyclic AMP; D004873:Ergolines; D008152:Loxapine; D008719:Methiothepin; D010636:Phenols; D010868:Pimozide; D010869:Pindolol; D010880:Piperidines; D011759:Pyrrolidines; D011985:Receptors, Serotonin; D016713:Ritanserin; D012701:Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013449:Sulfonamides; D014105:Tosyl Compounds; C111309:3,N-dimethyl-N-(1-methyl-3-(4-methylpiperidin-1-yl)propyl)benzenesulfonamide; D000096926:Benzenesulfonamides; C404922:SB 269970; C462239:SB258741; C104425:serotonin 7 receptor; C031649:mesulergine