Antagonism by SB 204070 of 5-HT-evoked contractions in the dog stomach: an in-vivo model of 5-HT4 receptor function.
The ability of 5-hydroxytryptamine (5-HT) to evoke contractile activity in the gastric Heidenhain pouch was measured in conscious dogs using a method in which 5-HT4 receptor-antagonist activity can be measured in-vivo. At doses of 5-HT which evoked short-lived measurable responses (5 or 10 micrograms kg-1, i.v.), it was found that this activity was greatly reduced by atropine (100 micrograms kg-1, i.v.), but was unaffected by methysergide, methiothepin, ketanserin (each at 100 micrograms kg-1, i.v.) or granisetron (10 or 100 micrograms kg-1, i.v.). At best SDZ 205-557 2-diethylaminoethyl-[2-methoxy-4-amino-5-chloro] benzoate; 100 micrograms kg-1, i.v.) reduced the action of 5-HT in 4/5 animals and increased it in the other but its effects were variable in magnitude and not consistently maintained. However, the more potent and selective 5-HT4-receptor antagonist SB 204070 (1-butyl-4-piperidinylmethyl 8-amino-7-chloro-1, 4-benzodioxan-5-carboxylate hydrochloride) dose-dependently antagonized the 5-HT-evoked contractions in all dogs tested. This action was reversible, but long-lasting with an effective half-life of 18.0h when administered at 1 microgram kg-1. The estimated ID50 value was 0.55 microgram kg-1.
Bingham
S
S
SmithKline Beecham Pharmaceuticals, Harlow, Essex, UK.
King
B F
BF
Rushant
B
B
Smith
M I
MI
Gaster
L
L
Sanger
G J
GJ
D010129:4-Aminobenzoic Acid / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001285:Atropine / Q000008:administration & dosage / Q000494:pharmacology; D004146:Dioxanes / Q000008:administration & dosage / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005753:Gastric Mucosa / Q000378:metabolism; D005769:Gastrointestinal Motility / Q000187:drug effects; D017829:Granisetron / Q000008:administration & dosage / Q000494:pharmacology; D007275:Injections, Intravenous; D007650:Ketanserin / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D008719:Methiothepin / Q000008:administration & dosage / Q000494:pharmacology; D008784:Methysergide / Q000008:administration & dosage / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D011897:Random Allocation; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D012701:Serotonin / Q000008:administration & dosage / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D013270:Stomach / Q000187:drug effects*; D062366:para-Aminobenzoates
D010129:4-Aminobenzoic Acid; D001285:Atropine; D004146:Dioxanes; D017829:Granisetron; D007650:Ketanserin; D008719:Methiothepin; D008784:Methysergide; D010880:Piperidines; D011985:Receptors, Serotonin; D012701:Serotonin; D012702:Serotonin Antagonists; D062366:para-Aminobenzoates; C072790:2-methoxy-4-amino-5-chlorobenzoic acid 2-(diethylamino)ethyl ester; C084858:SB 204070A