Activation of a wide range of serotonin receptors by serotonin itself or by certain prokinetic drugs results in enhanced gastrointestinal motility. Other prokinetic drugs may increase
acetylcholine concentrations by stimulating the
M1 receptor which causes acetylcholine release, or by
inhibiting the
enzyme acetylcholinesterase which metabolizes acetylcholine. Higher acetylcholine levels increase gastrointestinal
peristalsis and further increase pressure on the lower esophageal sphincter, thereby stimulating gastrointestinal motility, accelerating gastric emptying, and improving gastro-duodenal coordination. The
5-HT4 receptor is thought to play a significant role in both the
physiology and
pathophysiology of GI tract motility. Therefore, 5-HT4 receptors have been identified as potential therapeutic targets for diseases related to
GI dysmotility such as chronic
constipation. Some of these prokinetic agents, such as
mosapride and
cisapride, classic
benzamides, have only moderate affinity for 5HT4 receptors. In recent years, it has become clear that the selectivity profile is a major determinant of the risk-benefit profile of this class of agent. As such, the relatively poor selectivity profile of cisapride versus other receptors (especially
hERG [human ether-a-go-go K+] channels) contributes to its potential to cause
cardiac arrhythmias.
Prucalopride, a first in class
benzofuran, is a selective, high affinity
serotonin (5-HT4) receptor
agonist that stimulates colonic mass movements, which provide the main propulsive force to
defecation.
SSRIs have been found to have prokinetic actions on the small intestine. Other molecules, including macrolides such as
mitemcinal and
erythromycin, have affinity for the motilin receptor where they act as agonists resulting in prokinetic properties. ==Research==