Pharmacological comparison between [3H]GR 113808 binding sites and functional 5-HT4 receptors in neurons

Eur J Pharmacol. 1996 Mar 7;298(2):165-74. doi: 10.1016/0014-2999(95)00786-5.


5-HT4 receptors positively coupled to adenylyl cyclase and possessing unique pharmacological properties were first described in mouse colliculi neurons using functional studies. The recent introduction of a radiolabeled 5-HT4 receptor antagonist, [3H]GR 113808 [1-[2-(methylsulphonylamino)ethyl]4-piperidinyl]methyl-1-methyl-in dole-3 carboxylate] having high specificity and affinity allowed the pharmacological comparison between the specific binding sites identified with this compound and the functional 5-HT4 receptors in the same preparation, the colliculi neurons. We show here that [3H]GR 113808 binding is saturable in this preparation and reveals a homogeneous population of sites with a pKd value of 9.5 +/- 0.2 and a Bmax of 75 +/- 23 fmol/mg protein. Seventeen agonists and six antagonists with molecules structurally related either to indoles, benzamides or benzimidazolones and previously known as 5-HT4 receptor ligands, were tested for their ability to compete with [3H]GR 113808 binding sites and to stimulate or inhibit 5-HT-stimulated adenylyl cyclase activity. Highly significant correlations were obtained between the affinities of either agonists or antagonists for [3H]GR 113808 binding sites and their potencies for functional 5-HT4 receptors (r = 0.87 and 0.99, respectively). In addition, we also found good correlations between the Kd of several 5-HT4 receptor ligands determined in cell membranes of mouse colliculi neurons and their Kd determined in previous studies in guinea-pig striatum (0.95) and in human caudate (0.97). [3H]GR 113808 binding studies demonstrated that the 50% decrease in 5-HT-stimulated cAMP accumulation which followed a 5 min exposure period with 5-HT (10 microM) was not accompanied by any significant decrease in the number of binding sites. Longer exposure periods with 5-HT resulted in a decrease in [3H]GR 113808 binding sites which started to be significant after 30 min.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Cells, Cultured / drug effects
  • Dose-Response Relationship, Drug
  • Indoles / pharmacology*
  • Mice
  • Mice, Inbred Strains
  • Neurons / drug effects*
  • Receptors, Serotonin / drug effects*
  • Serotonin Antagonists / pharmacology*
  • Sulfonamides / pharmacology*


  • Indoles
  • Receptors, Serotonin
  • Serotonin Antagonists
  • Sulfonamides
  • GR 113808