SC-49518 enhances gastric emptying of solid and liquid meals and stimulates gastrointestinal motility in dogs by a 5-hydroxytryptamine4 receptor mechanism.
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)
Gastrointestinal Diseases Research Department, G.D. Searle and Co., Skokie, Illinois.
G W
GW
Gullikson
M A
MA
Virina
R F
RF
Loeffler
D C
DC
Yang
B
B
Goldstin
S X
SX
Wang
C
C
Moummi
D L
DL
Flynn
D L
DL
Zabrowski
D000818:Animals; D000932:Antiemetics / Q000494:pharmacology; D001549:Benzamides / Q000378:metabolism / Q000494:pharmacology*; D004285:Dogs; D004566:Electrodes; D004947:Esophagus / Q000187:drug effects / Q000502:physiology; D005260:Female; D005502:Food; D005746:Gastric Emptying / Q000187:drug effects*; D005769:Gastrointestinal Motility / Q000187:drug effects*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007422:Intestines / Q000187:drug effects / Q000502:physiology; D008297:Male; D008954:Models, Biological; D009043:Motor Activity / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D011706:Pyloric Antrum / Q000187:drug effects / Q000502:physiology; D011758:Pyrroles / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000378:metabolism; D011985:Receptors, Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013268:Stimulation, Chemical
D000932:Antiemetics; D001549:Benzamides; D011758:Pyrroles; D011956:Receptors, Cell Surface; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C079311:N-(exo-(hexahydro-1H-pyrrolizine-1-yl)methyl)-2-methoxy-4-amino-5-chlorobenzamide