Effect of a series of 5-HT4 receptor agonists and antagonists on steroid secretion by the adrenal gland in vitro.
We have previously shown that serotonin (5-hydroxytryptamine, 5-HT) stimulate corticosterone and aldosterone secretion from perifused frog adrenal gland in vitro through activation of 5-HT4 receptors. In the present study, we have used this model to investigate the effect of newly discovered 5-HT4 receptor agonists and antagonists on corticosteroid secretion. Serotonin, the benzamide derivatives (R,S)-zacopride ((R,S)-4-amino-N-(1- azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamide, HCI) and its enantiomers, the azabicycloalkyl benzimidazole derivatives BIMU 1 (endo-N- (8-methyl-8-azabicyclo-[3.2.1]oct-3-yl)-2,3-dihydro-3-ethyl-2-oxo- 1H-benzimidazole-1-carboxamide, HCl) and BIMU 8 (endo-N-(8-methyl-8- azabicyclo-[3.2.1]oct-3-yl)-2,3-dihydro-(1-methyl)ethyl-2-oxo-1H- benzimidazole-1-carboxamide, HCl) were all capable of enhancing corticosterone and aldosterone secretion in a dose-dependent manner. Serotonin was the most potent stimulator of steroidogenesis (EC50 = 1.5 x 10(-7) M) while the potency of the benzamide and the benzimidazolone derivatives was approximately 10 times lower. The rank order of efficacy of the different 5-HT4 receptor agonists was: (S)-zacopride > BIMU 8 = (R,S)-zacopride > BIMU 1 = (R)-zacopride = 5-HT. The stimulatory effects of 5-HT and the benzimidazolone derivatives on corticosteroid secretion were not additive, suggesting that they activated the same receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
Contesse
V
V
European Institute for Peptide Research, INSERM U 413, UA CNRS, University of Rouen, Mont-Saint-Aignan, France.
Hamel
C
C
Delarue
C
C
Lefebvre
H
H
Vaudry
H
H
D000311:Adrenal Glands / Q000187:drug effects* / Q000378:metabolism; D000450:Aldosterone / Q000378:metabolism*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003345:Corticosterone / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000494:pharmacology; D008297:Male; D011869:Radioligand Assay; D011898:Ranidae; D011985:Receptors, Serotonin / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology; D000077526:Tropisetron
D001549:Benzamides; D001562:Benzimidazoles; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007211:Indoles; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013449:Sulfonamides; C074390:DAU 6285; C070187:(endo-N-8-methyl-8-azabicyclo(3.2.1)oct-3-yl)-2,3-dihydro-3-ethyl-2-oxo-1H-benzimidazol-1-carboxamide; C070189:(endo-N-8-methyl-8-azabicyclo-(3.2.1)oct-3-yl)-2,3-dihydro-3-isopropyl-2-oxo-1H-benzimidazol-1-carboxamide; D012701:Serotonin; D000450:Aldosterone; D000077526:Tropisetron; C055971:zacopride; D003345:Corticosterone; C082871:GR 113808