Differential inverse agonist efficacies of SB-258719, SB-258741 and SB-269970 at human recombinant serotonin 5-HT7 receptors

Eur J Pharmacol. 2004 Jul 14;495(2-3):97-102. doi: 10.1016/j.ejphar.2004.05.033.

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.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Binding, Competitive / drug effects
  • CHO Cells
  • Clozapine / pharmacology
  • Cricetinae
  • Cricetulus
  • Cyclic AMP / metabolism
  • Dose-Response Relationship, Drug
  • Ergolines / pharmacology
  • Humans
  • Loxapine / pharmacology
  • Methiothepin / pharmacology
  • Phenols / pharmacology
  • Pimozide / pharmacology
  • Pindolol / pharmacology
  • Piperidines / pharmacology
  • Plasmids / genetics
  • Pyrrolidines / pharmacology
  • Radioligand Assay
  • Receptors, Serotonin / genetics
  • Receptors, Serotonin / metabolism*
  • Ritanserin / pharmacology
  • Serotonin / pharmacology
  • Serotonin Antagonists / pharmacology*
  • Serotonin Receptor Agonists / pharmacology*
  • Sulfonamides / pharmacology
  • Tosyl Compounds / pharmacology
  • Transfection

Substances

  • 3,N-dimethyl-N-(1-methyl-3-(4-methylpiperidin-1-yl)propyl)benzenesulfonamide
  • Ergolines
  • Phenols
  • Piperidines
  • Pyrrolidines
  • Receptors, Serotonin
  • SB 269970
  • SB258741
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • Sulfonamides
  • Tosyl Compounds
  • serotonin 7 receptor
  • Ritanserin
  • Pimozide
  • Serotonin
  • Methiothepin
  • Pindolol
  • Cyclic AMP
  • Clozapine
  • Loxapine
  • mesulergine