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6.30.7.1 Prokinetic Agents

6.30.7.1.1 Growth hormone secretagog receptor agonists

Ghrelin is the endogenous ligand for the growth hormone secretagog receptor. In addition to its well-described role in regulating pituitary growth hormone release, this receptor is expressed on motor neurons in the enteric nervous system and there is increasing evidence that activation of these receptors can increase GI motility. Ghrelin administration increases gastric emptying in an animal model of gastroparesis,101 an effect that has been replicated in healthy human subjects102 and in patients with either idiopathic103 or diabetic gastroparesis,4 where administration of human recombinant ghrelin enhanced gastric emptying.

The synthetic ghrelin analog RC-1139 (structure not disclosed) is a potent prokinetic agent in rat, increasing gastric emptying and reversing postoperative gastroparesis.104 Similarly, the ghrelin mimetic capromorelin (54) potently increases gastric emptying in mice.105 In rats, another synthetic ghrelin agonist, CP-464,709 (55), has potent prokinetic activity, increasing gastric emptying of a semisolid mixed nutrient meal with efficacy at least equal to that of metoclopramide.106 TZP-101, a macrocylic peptide analog (structure not disclosed), a novel, high-affinity ghrelin receptor agonist, dose-dependently increases gastric emptying in a rat model of gastric emptying of a liquid, nonnutrient meal.107 In a rat model of postoperative ileus, TZP-101 normalizes the delay in gastric emptying and accelerates delayed small intestinal transit.108 Additional novel ghrelin agonists, LY-444711 (56), L-692,429 (57), and ibutamoren (MK-677, 58), have appeared in the literature, although their effects on GI motility have not yet been described.1 ,11

54 Capromorelin

55 CP-464,709

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54 Capromorelin

55 CP-464,709

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