Relationship of serotonin-3 receptor antagonist activity to gastric emptying and motor-stimulating actions of prokinetic drugs in dogs.
Drugs that enhance gastrointestinal motility include the benzamide drugs metoclopramide, cisapride and renzapride (BRL-24924). Because these agents also are serotonin-3 (5-HT3) receptor antagonists, which can promote gastric emptying in some species, the motor-stimulating properties of benzamide agents may be due to this mechanism. Metoclopramide (0.3-3.0 mg/kg i.v.), cisapride (0.03-1.0 mg/kg i.v.) and BRL-24924 (0.01-0.1 mg/kg i.v.) were evaluated for their relative motility-stimulating and 5-HT3 receptor antagonist activities in conscious dogs and were compared with selective 5-HT3 antagonist antiemetic compounds ICS-205-930, (3 alpha-tropanyl)1-H-indole-3-carboxylic acid ester and granisetron (BRL-43694). Gastric antral contractions and intestinal myoelectric motility were determined in response to drugs, as were their effects on solid and liquid emptying in a gamma scintigraphic model of gastroparesis. 5-HT3 receptor antagonist potency was examined by deriving ED50 values for inhibition of cisplatin emesis. All drugs were 5-HT3 antagonists as they blocked cisplatin emesis with relative potencies of BRL-43694 = ICS-205-930 greater than BRL-24924 greater than cisapride = metoclopramide. The order of potency for stimulating fasted dog antral contractile activity, however, was BRL-24924 = cisapride greater than metoclopramide greater than ICS-205-930 = BRL-43694. Maximally effective doses of BRL-24924 (0.1 mg/kg i.v.) and cisapride (0.67 mg/kg i.v.) in the antrum also stimulated intestinal myoelectrical activity, whereas ICS-205-930 (0.5 and 2.0 mg/kg i.v.) was not active.(ABSTRACT TRUNCATED AT 250 WORDS)
Gullikson
G W
GW
Gastrointestinal Diseases Research Department, G. D. Searle Co., Skokie, Illinois.
Loeffler
R F
RF
Viriña
M A
MA
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D020117:Cisapride; D002945:Cisplatin / Q000037:antagonists & inhibitors; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D005746:Gastric Emptying / Q000187:drug effects*; D005769:Gastrointestinal Motility / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology; D007275:Injections, Intravenous; D008297:Male; D008787:Metoclopramide / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D000077526:Tropisetron
D001549:Benzamides; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007211:Indoles; D010880:Piperidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D000077526:Tropisetron; C053006:renzapride; D008787:Metoclopramide; D002945:Cisplatin; D020117:Cisapride