Résumé
5-HT
4 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-HT
4 receptor antagonist, [
3H]GR 113808 [1-[2-(methylsulphonylamino)ethyl]4-piperidinyl]methyl-1-methyl-indole-3 carboxylate] having high specificity and affinity allowed the pharmacological comparison between the specific binding sites identified with this compound and the functional 5-HT
4 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 p
K
d value of 9.5 ± 0.2 and a
B
max 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-HT
4 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-HT
4 receptors (
r = 0.87 and 0.99, respectively). In addition, we also found good correlations between the
K
d of several 5-HT
4 receptor ligands determined in cell membranes of mouse colliculi neurons and their
K
d 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 μM) 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.