ABSTRACT
SC-49518 (N-[exo-(hexahydro-1H-pyrrolizine-1-yl)methyl]-2-methoxy-4- amino-5-chlorobenzamide HCl), a new benzamide gastrointestinal prokinetic compound, was investigated to determine its ability to stimulate gastrointestinal motility in vivo and whether these actions could be mediated by agonist activity at the putative 5-hydroxytryptamine (5-HT)4 receptor. In conscious fasted dogs with strain gauge transducers and myoelectrodes, SC-49518 disrupted gastric and small intestinal migrating motility complex cycling for more than 3.5 hr. It stimulated gastric antral contractile and intestinal myoelectric spike burst activities during the normally quiescent Phase I of the migrating motility complex at doses as low as 0.01 and 0.03 mg/kg i.v., respectively. In a canine model of gastroparesis, SC-49518 reversed completely alpha-2 adrenergically delayed gastric emptying of a solid meal with an ED50 value of 0.1 mg/kg intragastrically and partially reversed delayed emptying of a liquid meal. SC-49518, like 5-HT, cisapride and renzapride, acted as an agonist (EC50 = 6.6 +/- 1.1 x 10(-8) M) at the putative 5-HT4 receptor in rat esophageal tunica muscularis mucosae by relaxing carbachol-induced contractions. SC-49518 was a partial agonist at 5-HT4 receptors, but also blocked high affinity (5-HT4-mediated) responses to 5-HT (10(-9) M to 3 x 10(-7) M) in guinea pig ileum with a pA2 value of 8.39.(ABSTRACT TRUNCATED AT 250 WORDS)
Subject(s)
Benzamides/pharmacology , Gastric Emptying/drug effects , Gastrointestinal Motility/drug effects , Pyrroles/pharmacology , Receptors, Serotonin/physiology , Animals , Antiemetics/pharmacology , Benzamides/metabolism , Dogs , Electrodes , Esophagus/drug effects , Esophagus/physiology , Female , Food , Guinea Pigs , In Vitro Techniques , Intestines/drug effects , Intestines/physiology , Male , Models, Biological , Motor Activity/drug effects , Muscle Contraction/drug effects , Pyloric Antrum/drug effects , Pyloric Antrum/physiology , Pyrroles/metabolism , Rats , Rats, Wistar , Receptors, Cell Surface/metabolism , Serotonin Antagonists , Serotonin Receptor Agonists/pharmacology , Stimulation, ChemicalABSTRACT
Motility-stimulating drugs can increase gastric antral and intestinal contractions but do not usually enhance emptying unless gastroparesis is present. An alpha 2-adrenergic agonist (SC-39585A) was used to inhibit antroduodenal motility and simulate gastroparesis in dogs. SC-39585A caused dose-related inhibition of emptying of solid and liquid meals as well as the antral and duodenal motility responses to the solid meal. The motility-enhancing agent renzapride (100 micrograms/kg iv) did not enhance emptying of the solid meal under nondelayed conditions. However, at the same dose it partially reversed the delay in solid emptying but only when antroduodenal motility was incompletely (30 micrograms/kg sc) and not totally (100 micrograms/kg sc) inhibited by SC-39585A. This was done in part by antagonizing antral but not duodenal inhibition of motility. Renzapride was also effective orally in reversing the delay in solid emptying. Similarly, renzapride reversed the delay in liquid emptying caused by SC-39585A (30 micrograms/kg sc). An alpha 2-adrenergic agonist can be used to model gastroparesis in dogs by inhibiting antroduodenal motility and can also be used to examine the actions of motor stimulants, such as renzapride, which promote gastric emptying.
Subject(s)
Adrenergic alpha-Agonists/pharmacology , Benzamides/pharmacology , Bridged Bicyclo Compounds, Heterocyclic , Bridged Bicyclo Compounds/pharmacology , Cresols/pharmacology , Gastric Emptying/drug effects , Gastrointestinal Motility/drug effects , Paralysis/physiopathology , Pyrroles/pharmacology , Receptors, Adrenergic, alpha/physiology , Stomach Diseases/physiopathology , Animals , Disease Models, Animal , Dogs , Duodenum/drug effects , Duodenum/physiology , Duodenum/physiopathology , Eating , Muscle, Smooth/drug effects , Muscle, Smooth/physiology , Muscle, Smooth/physiopathology , Receptors, Adrenergic, alpha/drug effects , Serotonin Antagonists , Technetium Tc 99m Sulfur ColloidABSTRACT
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)
