SC-53606, a potent and selective antagonist of 5-hydroxytryptamine4 receptors in isolated rat esophageal tunica muscularis mucosae.
(1-S,8-S)-N-[(hexahydro-1H-pyrrolizin-1-yl)methyl]-6-chloroimi+ ++- dazo[1,2-a]pyridine-8-carboxamide hydrochloride (SC-53606) acts as an antagonist of 5-hydroxytryptamine4 (5-HT4) receptor-mediated relaxation of carbachol-induced contractions in rat esophageal tunica muscular mucosae, but does not possess 5-HT4 agonist activity. SC-53606 demonstrated a pA2 value against 5-HT in this tissue of 7.91 +/- 0.08 (Ki = 12.3 +/- 1.17 nM). Similar pA2 values of 7.68 +/- 0.06, 7.67 +/- 0.06 and 7.63 +/- 0.05 were determined for the synthetic 5-HT4 receptor agonists SC-53116, 5-methoxytryptamine and renzapride, respectively. In addition, slopes of Schild plots for antagonism of these four agonists by SC-53606 were 1.07 +/- 0.02, 0.98 +/- 0.03, 1.04 +/- 0.02 and 0.96 +/- 0.06, respectively, and did not deviate from unity. The pA2 values for 5-HT4 antagonism against 5-HT were determined to be 6.80 +/- 0.09 for tropisetron and 7.36 +/- 0.08 for 2-methoxy-4-amino-S- chlorobenzoic acid-2-(diethylamino)ethyl ester SDZ 205-557), indicating that SC-53606 is more a potent 5-HT4 antagonist than either of the reference antagonists. Radioligand binding studies also demonstrated that SC-53606 is a selective antagonist with more affinity for 5-HT4 than for other 5-HT receptors. Displacement of radioligand binding from 5-HT1 and 5-HT2 receptors by SC-53606 was less than 50% at a 10 microM concentration. Similarly, SC-53606 displayed little binding affinity at alpha 1, alpha 2 and beta adrenergic, dopamine1, dopamine2 and muscarinic cholinergic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Neurological Diseases Research, G.D. Searle & Company, Skokie, Illinois.
D C
DC
Yang
B
B
Goldstin
A E
AE
Moormann
D L
DL
Flynn
G W
GW
Gullikson
D010129:4-Aminobenzoic Acid / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002217:Carbachol / Q000494:pharmacology; D004947:Esophagus / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure*; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009092:Mucous Membrane / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D011758:Pyrroles / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011956:Receptors, Cell Surface / Q000187:drug effects; D011985:Receptors, Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D000077526:Tropisetron; D014363:Tryptamines / Q000494:pharmacology; D062366:para-Aminobenzoates
D001549:Benzamides; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007093:Imidazoles; D007211:Indoles; D011758:Pyrroles; D011956:Receptors, Cell Surface; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; D062366:para-Aminobenzoates; C072790:2-methoxy-4-amino-5-chlorobenzoic acid 2-(diethylamino)ethyl ester; C074211:SC 53116; C083229:SC 53606; C027552:5-methyltryptamine; D000077526:Tropisetron; D002217:Carbachol; C053006:renzapride; D010129:4-Aminobenzoic Acid