Antagonists of 5-HT4 receptor-mediated responses in adult hippocampal neurons
Torres, G.E.; Holt, I.L.; Andrade, R.
Journal of Pharmacology and Experimental Therapeutics 271(1): 255-261
1994
ISSN/ISBN: 0022-3565 PMID: 7965722 Document Number: 434325
The study of serotonin-4 (5-HT-4) receptors in the central nervous system has been hindered by the lack of effective, selective antagonists. However, recently, several novel compounds have been synthesized and shown to act as antagonists at 5-HT-4 receptors in smooth muscle and embryonic neurons in culture. In the present study, intracellular electrophysiological recordings were used to test the effects of three of these compounds: endo-8-methyl-8-azabicyclo(3.2.1)oct-3-yl-2,3-dihydro-6-methoxy-2-oxo-1H-benzimidazole-1-carboxylate (DAU 6285), (1-(2-(methylsulfonylamino)ethyl)-4-piperidinyl)methyl 1-methyl-1H-indole-3-carboxylate (GR 113808) and 2-diethylaminoethyl-(2-methoxy-4-amino-5-chloro) benzoate (SDZ 205-557) on the 5-HT-4 reduction of the afterhyperpolarization seen in adult CA1 hippocampal neurons in brain slices. GR 113808, SDZ 205-557 and DAU 6285 all functioned as competitive antagonists at these 5-HT-4 receptors. Although all three compounds tested acted as effective antagonists, they differed considerably in potency. When the potency of these antagonists at the 5-HT-4 receptor that mediates the reduction of the afterhyperpolarization was compared with that observed for 5-HT-4 receptors in biochemical and binding assays, an excellent correlation was observed. Among the antagonists tested, GR 113808 was the most potent (pA-2 = GR 113808 gt SDZ 205-507 gt DAU 6285). It exhibited an apparent affinity for the 5-HT-4 receptors in the low nanomolar range but did not antagonize 5-HT-1A, beta-adrenergic or muscarinic receptor-mediated responses when applied at concentrations two orders of magnitude higher. These results demonstrate the usefulness of these compounds in the physiological identification of 5-HT-4 receptor-mediated responses in central neurons. The availability of these antagonists should greatly facilitate the identification of additional 5-HT-4-mediated responses in the adult central nervous system.