Target Validation Information
Target ID T59604
Target Name Growth hormone secretagogue receptor type 1
Target Type
Successful
Drug Potency against Target RPKPfQwFwLL-NH2 Drug Info IC50 = 3.2 nM [528740]
WFwLL-NH2 Drug Info IC50 = 530 nM [528740]
RwFwLL-NH2 Drug Info IC50 = 12 nM [528740]
WFwGG-NH2 Drug Info IC50 = 540 nM [528740]
HwFwLL-NH2 Drug Info IC50 = 58 nM [528740]
AwFwLL-NH2 Drug Info IC50 = 15 nM [528740]
QwFwLL-NH2 Drug Info IC50 = 120 nM [528740]
RQ-00000005 Drug Info IC50 = 3000 nM [525674]
4-(3-hexylureido)-N-phenylbenzenesulfonamide Drug Info IC50 = 4300 nM [530395]
DprwFwLL-NH2 Drug Info IC50 = 210 nM [528740]
KwFwLL-NH2 Drug Info IC50 = 32 nM [528740]
DwFwLL-NH2 Drug Info IC50 = 60 nM [528740]
TZP-101 Drug Info EC50 = 29 nM [552859]
Action against Disease Model TZP-101 Previously we have shown in a rodent model of postoperative ileus that the synthetic ghrelin receptor agonist TZP-101 prevents the delay in gastric emptying and improves small intestinal transit. The goal of the present study was to investigate whether TZP-101 affects colonic transit and food intake in rats with postoperative ileus. TZP-101 (0.03-1 mg/kg) dose-dependently decreased the time to first bowel movement and increased fecal pellet output measured at 12 h and 24 h post-surgery compared to the vehicle. The administration of TZP-101 was not associated with a significant alteration in food intake. [537004] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations The present study examined the role of ghrelin in producing normal metabolic and neurochemical responses to chronic stress. This was achieved by examining these responses in mice with targeted deletions of the ghrelin receptor gene (GHSR KO mice), and comparing them with the same responses in their wild-type (WT) littermates. As expected, WT stressed mice decreased their caloric intake, body weight gain and caloric efficiency while maintaining adiposity. GHSR KO mice, however, did not show these alterations despite having normal glucocorticoid responses to stress. In parallel with these changes, chronic unpredictable stress caused changes in norepinephrine, dopamine and serotonin in a n uMber of brain regions. Of these, norepinephrine neurotransmission in the arcuatenucleus and prefrontal cortex was differentially altered in GHSR KO mice. Within the nucleus ac uMbens, dopamine utilization was increased in WT mice but not in GHSR KO mice. Finally, there were strain differences in serotonin neurotransmission that may explain interstrain body weight and adiposity differences. These results suggest that the metabolic changes necessary to deal with the energetic challenge presented by repeated exposure to stressors do not occur in GHSR KO mice, and they are discussed within the context of the potential vulnerability to stress-induced pathology [528740]
References
Ref 528740J Biol Chem. 2007 May 25;282(21):15799-811. Epub 2007 Mar 19.Identification of an efficacy switch region in the ghrelin receptor responsible for interchange between agonism and inverse agonism.
Ref 528740J Biol Chem. 2007 May 25;282(21):15799-811. Epub 2007 Mar 19.Identification of an efficacy switch region in the ghrelin receptor responsible for interchange between agonism and inverse agonism.
Ref 528740J Biol Chem. 2007 May 25;282(21):15799-811. Epub 2007 Mar 19.Identification of an efficacy switch region in the ghrelin receptor responsible for interchange between agonism and inverse agonism.
Ref 528740J Biol Chem. 2007 May 25;282(21):15799-811. Epub 2007 Mar 19.Identification of an efficacy switch region in the ghrelin receptor responsible for interchange between agonism and inverse agonism.
Ref 528740J Biol Chem. 2007 May 25;282(21):15799-811. Epub 2007 Mar 19.Identification of an efficacy switch region in the ghrelin receptor responsible for interchange between agonism and inverse agonism.
Ref 528740J Biol Chem. 2007 May 25;282(21):15799-811. Epub 2007 Mar 19.Identification of an efficacy switch region in the ghrelin receptor responsible for interchange between agonism and inverse agonism.
Ref 528740J Biol Chem. 2007 May 25;282(21):15799-811. Epub 2007 Mar 19.Identification of an efficacy switch region in the ghrelin receptor responsible for interchange between agonism and inverse agonism.
Ref 525674Bioorg Med Chem Lett. 2000 Jan 3;10(1):5-8.Modeling directed design and biological evaluation of quinazolinones as non-peptidic growth hormone secretagogues.
Ref 537004Effect of the ghrelin receptor agonist TZP-101 on colonic transit in a rat model of postoperative ileus. Eur J Pharmacol. 2009 Feb 14;604(1-3):132-7. Epub 2008 Dec 14.
Ref 530395Bioorg Med Chem Lett. 2009 Nov 1;19(21):6237-40. Epub 2009 Aug 26.Discovery and optimization of novel 4-[(aminocarbonyl)amino]-N-[4-(2-aminoethyl)phenyl]benzenesulfonamide ghrelin receptor antagonists.
Ref 528740J Biol Chem. 2007 May 25;282(21):15799-811. Epub 2007 Mar 19.Identification of an efficacy switch region in the ghrelin receptor responsible for interchange between agonism and inverse agonism.
Ref 528740J Biol Chem. 2007 May 25;282(21):15799-811. Epub 2007 Mar 19.Identification of an efficacy switch region in the ghrelin receptor responsible for interchange between agonism and inverse agonism.
Ref 528740J Biol Chem. 2007 May 25;282(21):15799-811. Epub 2007 Mar 19.Identification of an efficacy switch region in the ghrelin receptor responsible for interchange between agonism and inverse agonism.
Ref 552859Pharmacological demarcation of the growth hormone, gut motility and feeding effects of ghrelin using a novel ghrelin receptor agonist. Endocrinology. 2008 Dec;149(12):6280-8. doi: 10.1210/en.2008-0804. Epub 2008 Aug 21.

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