Therapeutic Targets Database
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Target Validation Information
TTD IDTTDC00112
Target NameSomatostatin receptor type 1    
Type of TargetClinical trial target    
Drug Potency against TargetCAP-232IC50 = 0.1 nM[1]
PasireotideIC50 = 9.3 nM[2]
PasireotideKi = 9.3 nM[3]
PasireotideKi = 9.3 nM[4]
Somatostatin AnalogueIC50 = 0.297 nM[5]
Somatostatin AnalogueIC50 = 0.308 nM[5]
Somatostatin AnalogueIC50 = 0.397 nM[5]
Somatostatin AnalogueIC50 = 0.498 nM[5]
Des-AA5-[D-Trp8]SRIFIC50 = 0.98 nM[6]
Des-AA1,2,5-[D-Trp8,(NalphaMe)IAmp9]SRIFIC50 = 10 nM[6]
Des-AA1,2,5-[D-Trp8,Tyr11]SRIFIC50 = 10 nM[6]
Des-AA1,2,4,13-[D-Trp8]SRIFIC50 = 112 nM[7]
Des-AA1,2,5-[(NalphaMe)Cys3,D-Nal8,IAmp9]SRIFIC50 = 113 nM[6]
Des-AA1,2,5-[(NalphaMe)Cys3,D-Trp8,IAmp9]SRIFIC50 = 14 nM[6]
Des-AA1,5-[Tyr2,D-Trp8,IAmp9]SRIF CH-288IC50 = 14 nM[7]
Des-AA1,2,5-[IAmp9,Tyr11]-SRIFIC50 = 15 nM[6]
Des-AA1,5-[Tyr2,D-Trp8,IAmp9]Cbm-SRIFIC50 = 15 nM[6]
Des-AA1,2,5-[D-Trp8,IAmp9,(NalphaMe)Cys14]SRIFIC50 = 151 nM[6]
Des-AA1,5-[Tyr2,D-Trp8,(NalphaMe)IAmp9]SRIFIC50 = 16 nM[6]
Des-AA1,2,5-[D-Nal8,IAmp9,(NalphaMe)Thr12]SRIFIC50 = 176 nM[6]
Des-AA1,2,5,12,13-[D-Trp8,IAmp9]SRIFIC50 = 189 nM[7]
Des-AA1,2,4,5,13-[D-Trp8]-SRIFIC50 = 197 nM[7]
SRIF-28IC50 = 2.3 nM[8]
Des-AA1,2,5-[D-Trp8,IAmp9,m-I-Tyr11]Cbm-SRIFIC50 = 2.5 nM[6]
CytotoxinPeptide ConjugateIC50 = 2.79 nM[9]
Des-AA1,2,5-[D-Trp8,IAmp9,(NalphaMe)Ser13]SRIFIC50 = 23 nM[6]
Des-AA1,2,5-[D-Nal8,IAmp9]SRIFIC50 = 248 nM[6]
Des-AA1,2,5-[D-Nal8,(NalphaMe)IAmp9,Tyr11]SRIFIC50 = 25 nM[6]
Des-AA1,2,5-[D-Nal8,IAmp9,(NalphaMe)Cys14]SRIFIC50 = 260 nM[6]
ODT-8IC50 = 27 nM[7]
Des-AA1,2,5-[(NalphaMe)D-Nal8,IAmp9]SRIFIC50 = 325 nM[6]
Des-AA1,2,5-[D-Trp8,IAmp9]SRIF CH-275IC50 = 33 nM[6]
Des-AA1,5-[Tyr2,D-Trp8,(NalphaMe)IAmp9]Cbm-SRIFIC50 = 45 nM[6]
Des-AA1,2,5,12,13-[D-Trp8]SRIFIC50 = 5.3 nM[7]
Des-AA1,2,5-[(NalphaMe)Lys4,D-Nal8,IAmp9]SRIFIC50 = 535 nM[6]
CytotoxinPeptide ConjugateIC50 = 54.2 nM[9]
CytotoxinPeptide ConjugateIC50 = 571 nM[9]
Des-AA1,2,5-[D-Nal8,IAmp9,(NalphaMe)Phe11]SRIFIC50 = 583 nM[6]
Des-AA1,2,4,12,13-[D-Trp8]SRIFIC50 = 59 nM[7]
Des-AA1,2,5-[D-Nal8,(NalphaMe)IAmp9]SRIFIC50 = 69 nM[6]
Des-AA1,2,5-[D-Trp8,(NalphaMe)IAmp9,Tyr11]SRIFIC50 = 7.2 nM[6]
Des-AA1,2,5-[D-Nal8,IAmp9,(NalphaMe)Ser13]SRIFIC50 = 71 nM[6]
Des-AA1,4,5,13-[Tyr2,D-Trp8]-SRIFIC50 = 720 nM[7]
Des-AA1,2,5-[D-Trp8,IAmp9,(NalphaMe)Thr12]SRIFIC50 = 75 nM[6]
Des-AA1,2,4,5-[D-Trp8]SRIFIC50 = 79 nM[7]
Des-AA1,2,5-[D-Trp8,IAmp9,Tyr11]Cbm-SRIFIC50 = 8 nM[6]
SOMATOSTATINKi = 2.3 nM[10]
Action against Disease ModelPasireotideIn the presence of octreotide or SS-14, SOM230 showed partial agonist behavior, inhibiting phosphorylation, and internalization of sst(2A). Upon overexpression of GRK2 or GRK3, pasireotide stimulated selective phosphorylation of Thr356 and Thr359 but not of Thr353 or Thr354 within the (353)TTETQRT(359) motif. Pasireotide-mediated phosphorylation led to the formation of relatively unstable beta-arrestin-sst(2A) complexes that dissociated at or near the plasma membrane. Thus, octreotide and pasireotide are equally active in inducing classical G protein-dependent signaling via the sst(2A) somatostatin receptor.[11]
The Effect of Target Knockout, Knockdown or Genetic VariationsIn the retina of wild type (WT) mice, sst1 receptors are localised to somatostatin-14(SRIF)-containing amacrine cells, whereas in the retina of sst1 KO mice, sst1 receptors are absent. sst1 receptor loss causes a significant increase in retinal levels of SRIF, whereas it does not affect SRIF messenger RNA indicating that sst1 receptors play a role in limiting retinal SRIF at the post-transcriptional level. As another consequence of sst1 receptor loss, levels of expression of sst2 receptors are significantly higher than in control retinas. Together, these findings provide the first demonstration of prominent compensatory regulation in the mouse retina as a consequence of a distinct SRIF receptor deletion. The fact that in the absence of the sst1 receptor, retinal SRIF increases in concomitance with an increase in sst2 receptors suggests that SRIF may regulate sst2 receptor expression and that this regulatory process is controlled upstream by the sst1 receptor. This finding can be important in the design of drugs affecting SRIF function, not only in the retina, but also elsewhere in the brain[12]
Ref 1Comparison of the binding modes of TT-232 in somatostatin receptors type 1 and 4. Journal of Molecular Structure: THEOCHEM. Volume 816, Issues 1-3, 20 August 2007, Pages 73-76. To Reference
Ref 2Mol Cell Endocrinol. 2008 May 14;286(1-2):69-74. Epub 2007 Sep 19.Pasireotide (SOM230): development, mechanism of action and potential applications. To Reference
Ref 3J Med Chem. 2005 Oct 20;48(21):6523-43.Designed multiple ligands. An emerging drug discovery paradigm. To Reference
Ref 4Nat Rev Drug Discov. 2009 Jul;8(7):547-66.Cell cycle kinases as therapeutic targets for cancer. To Reference
Ref 5J Med Chem. 1999 Apr 22;42(8):1341-7.Comparison of four 64Cu-labeled somatostatin analogues in vitro and in a tumor-bearing rat model: evaluation of new derivatives for positron emission tomography imaging and targeted radiotherapy. To Reference
Ref 6J Med Chem. 2005 Jan 27;48(2):507-14.Somatostatin receptor 1 selective analogues: 2. N(alpha)-Methylated scan. To Reference
Ref 7J Med Chem. 2005 Jan 27;48(2):515-22.Somatostatin receptor 1 selective analogues: 3. Dicyclic peptides. To Reference
Ref 8J Med Chem. 2010 Aug 26;53(16):6188-97.Novel octreotide dicarba-analogues with high affinity and different selectivity for somatostatin receptors. To Reference
Ref 9Bioorg Med Chem Lett. 2003 Mar 10;13(5):799-803.An adjustable release rate linking strategy for cytotoxin-peptide conjugates. To Reference
Ref 10J Med Chem. 2005 Oct 20;48(21):6643-52.Discovery of iodinated somatostatin analogues selective for hsst2 and hsst5 with excellent inhibition of growth hormone and prolactin release from rat pituitary cells. To Reference
Ref 11Mol Endocrinol. 2010 Feb;24(2):436-46. Epub 2010 Jan 5.Pasireotide and octreotide stimulate distinct patterns of sst2A somatostatin receptor phosphorylation. To Reference
Ref 12Neuropharmacology. 2003 Dec;45(8):1080-92.Genetic deletion of somatostatin receptor 1 alters somatostatinergic transmission in the mouse retina. To Reference



 

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Professor in Department of Pharmacy
National University of Singapore, Singapore


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