Pharmacological comparison between [ super(3)H]GR 113808 binding sites and functional 5-HT sub(4) receptors in neurons

• Published in: European journal of pharmacology Vol. 298; no. 2; pp. 165 - 174
• Main Authors: Ansanay, H, Sebben, M, Bockaert, J, Dumuis, A
• Format: Journal Article
• Language: English
• Published: 01.03.1996
• ISSN: 0014-2999

5-HT sub(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 sub(4) receptor antagonist, [ super(3)H]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 sub(4) receptors in the same preparation, the colliculi neurons. We show here that [ super(3)H]GR 113808 binding is saturable in this preparation and reveals a homogeneous population of sites with a pK sub(d) value of 9.5 plus or minus 0.2 and a B sub(max) of 75 plus or minus 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 sub(4) receptor ligands, were tested for their ability to compete with [ super(3)H]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 [ super(3)H]GR 113808 binding sites and their potencies for functional 5-HT sub(4) receptors (r = 0.87 and 0.99, respectively). In addition, we also found good correlations between the K sub(d) of several 5-HT sub(4) receptor ligands determined in cell membranes of mouse colliculi neurons and their K sub(d) determined in previous studies in guinea-pig striatum (0.95) and in human caudate (0.97). [ super(3)H]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 mu M) was not accompanied by any significant decrease in the number of binding sites. Longer exposure periods with 5-HT resulted in a decrease in [ super(3)H]GR 113808 binding sites which started to be significant after 30 min.