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2D Structure
Also known as: Cyclic somatostatin, 38916-34-6, Somatostatine, Somatostatina, Somatostatinum, Somatostatin-14
Molecular Formula
C76H104N18O19S2
Molecular Weight
1637.9  g/mol
InChI Key
NHXLMOGPVYXJNR-ATOGVRKGSA-N

A 14-amino acid peptide named for its ability to inhibit pituitary GROWTH HORMONE release, also called somatotropin release-inhibiting factor. It is expressed in the central and peripheral nervous systems, the gut, and other organs. SRIF can also inhibit the release of THYROID-STIMULATING HORMONE; PROLACTIN; INSULIN; and GLUCAGON besides acting as a neurotransmitter and neuromodulator. In a number of species including humans, there is an additional form of somatostatin, SRIF-28 with a 14-amino acid extension at the N-terminal.
1 2D Structure

2D Structure

2 Identification
2.1 Computed Descriptors
2.1.1 IUPAC Name
(4R,7S,10S,13S,16S,19S,22S,25S,28S,31S,34S,37R)-19,34-bis(4-aminobutyl)-31-(2-amino-2-oxoethyl)-37-[[2-[[(2S)-2-aminopropanoyl]amino]acetyl]amino]-13,25,28-tribenzyl-10,16-bis[(1R)-1-hydroxyethyl]-7-(hydroxymethyl)-22-(1H-indol-3-ylmethyl)-6,9,12,15,18,21,24,27,30,33,36-undecaoxo-1,2-dithia-5,8,11,14,17,20,23,26,29,32,35-undecazacyclooctatriacontane-4-carboxylic acid
2.1.2 InChI
InChI=1S/C76H104N18O19S2/c1-41(79)64(100)82-37-61(99)83-58-39-114-115-40-59(76(112)113)92-72(108)57(38-95)91-75(111)63(43(3)97)94-71(107)54(33-46-23-11-6-12-24-46)90-74(110)62(42(2)96)93-66(102)51(28-16-18-30-78)84-69(105)55(34-47-36-81-49-26-14-13-25-48(47)49)88-68(104)53(32-45-21-9-5-10-22-45)86-67(103)52(31-44-19-7-4-8-20-44)87-70(106)56(35-60(80)98)89-65(101)50(85-73(58)109)27-15-17-29-77/h4-14,19-26,36,41-43,50-59,62-63,81,95-97H,15-18,27-35,37-40,77-79H2,1-3H3,(H2,80,98)(H,82,100)(H,83,99)(H,84,105)(H,85,109)(H,86,103)(H,87,106)(H,88,104)(H,89,101)(H,90,110)(H,91,111)(H,92,108)(H,93,102)(H,94,107)(H,112,113)/t41-,42+,43+,50-,51-,52-,53-,54-,55-,56-,57-,58-,59-,62-,63-/m0/s1
2.1.3 InChI Key
NHXLMOGPVYXJNR-ATOGVRKGSA-N
2.1.4 Canonical SMILES
CC(C1C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(CSSCC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)N1)CCCCN)CC2=CNC3=CC=CC=C32)CC4=CC=CC=C4)CC5=CC=CC=C5)CC(=O)N)CCCCN)NC(=O)CNC(=O)C(C)N)C(=O)O)CO)C(C)O)CC6=CC=CC=C6)O
2.1.5 Isomeric SMILES
C[C@H]([C@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N1)CCCCN)CC2=CNC3=CC=CC=C32)CC4=CC=CC=C4)CC5=CC=CC=C5)CC(=O)N)CCCCN)NC(=O)CNC(=O)[C@H](C)N)C(=O)O)CO)[C@@H](C)O)CC6=CC=CC=C6)O
2.2 Synonyms
2.2.1 MeSH Synonyms

1. Cyclic Somatostatin

2. Somatofalk

3. Somatostatin 14

4. Somatostatin, Cyclic

5. Somatostatin-14

6. Somatotropin Release Inhibiting Factor

7. Somatotropin Release Inhibiting Hormone

8. Somatotropin Release-inhibiting Factor

9. Somatotropin Release-inhibiting Hormone

10. Srih-14

11. Stilamin

2.2.2 Depositor-Supplied Synonyms

1. Cyclic Somatostatin

2. 38916-34-6

3. Somatostatine

4. Somatostatina

5. Somatostatinum

6. Somatostatin-14

7. Synthetic Somatostatin-14

8. Somatostatin (sheep)

9. Somatostatin 14

10. Synthetic Growth Hormone Release-inhibiting Hormone

11. Chebi:64628

12. Somatostatin, Cyclic

13. Stilamin

14. Srif 14

15. 15-28-somatostatin-28

16. Somatostatine [inn-french]

17. Somatostatinum [inn-latin]

18. Somatostatina [inn-spanish]

19. Somatostatin (rat)

20. Ccris 3629

21. Somatostatin (human)

22. Somatostatin (pigeon)

23. Einecs 254-186-5

24. Somatostatin [inn:ban]

25. Somatostatin-1

26. Unii-6e20216q0l

27. Sr 9357

28. Somatostatin-14srif-14

29. Chembl1823872

30. Schembl21361053

31. Bdbm81767

32. Growth Hormone Inhibiting Hormone

33. Akos015994634

34. 6e20216q0l

35. Db09099

36. Hs-2027

37. Ncgc00167137-01

38. Growth Hormone-release Inhibiting Factor: L-alanylglycyl-l-cysteinyl-l-lysyl-l-asparaginyl-l-phenylalanyl-l-phenylalanyl-l-tryptophyl-l-lysyl-l-threonyl-l-phenylalanyl-l-threonyl-l-seryl-l-cysteine Cyclic (3-14) Disulfide

39. Cas_38916-34-6

40. Cb6417646

41. C74981

42. 916s346

43. Brd-k14681867-015-01-6

44. Q22075835

45. Ala-gly-cyclo-[cys-lys-asn-phe-phe-trp-lys-thr-phe-thr-ser-cys]

46. L-alanyl-n-[(4r,7s,10s,13s,16s,19s,22s,25s,28s,31s,34s,37r)-19,34-bis(4-aminobutyl)-31-(2-amino-2-oxoethyl)-13,25,28-tribenzyl-4-carboxy-10,16-bis[(1r)-1-hydroxyethyl]-7-(hydroxymethyl)-22-(1h-indol-3-ylmethyl)-6,9,12,15,18,21,24,27,30,33,36-undecaoxo-1,2-dithia-5,8,11,14,17,20,23,26,29,32,35-undecaazacyclooctatriacontan-37-yl]glycinamide

47. L-alanylglycyl-l-cysteinyl-l-lysyl-l-asparaginyl-l-phenylalanyl-l-phenylalanyl-l-tryptophyl-l-lysyl-l-threonyl-l-phenylalanyl-l-threonyl-l-seryl-l-cysteine Cyclic (3-14) Disulfide

48. Somatostatin-14 (h-l-ala-l-gly-l-cys(1)-l-lys-l-asn-l-phe-l-phe-l-trp-l-lys-l-thr-l-phe-l-thr-l-ser-l-cys(1)-oh)

2.3 Create Date
2007-07-03
3 Chemical and Physical Properties
Molecular Weight 1637.9 g/mol
Molecular Formula C76H104N18O19S2
XLogP3-3.1
Hydrogen Bond Donor Count22
Hydrogen Bond Acceptor Count24
Rotatable Bond Count26
Exact Mass1636.71665551 g/mol
Monoisotopic Mass1636.71665551 g/mol
Topological Polar Surface Area664 Ų
Heavy Atom Count115
Formal Charge0
Complexity3240
Isotope Atom Count0
Defined Atom Stereocenter Count15
Undefined Atom Stereocenter Count0
Defined Bond Stereocenter Count0
Undefined Bond Stereocenter Count0
Covalently Bonded Unit Count1
4 Drug and Medication Information
4.1 Drug Indication

For the symptomatic treatment of acute bleeding from esophageal varices. Other treatment options for long-term management of the condition may be considered if necessary, once initial control has been established.


5 Pharmacology and Biochemistry
5.1 Pharmacology

Somatostatin is an endogenous peptide hormone that is secreted by the central nervous system, gastrointestinal tract, retina, peripheral neurons and pancreatic D cells of the islets of Langerhans. It exhibits several biological roles but predominantly exerts an inhibitory effect on secretion of other hormones and transmitters. While distribution of two active isoforms of somatostatin is similar, SST-14 is more predominant in the enteric neurons and peripheral nerves whereas SST-28 is more prominent in the retina and intestinal mucosal cells. **Anterior pituitary gland and brain:** It inhibits the release of growth hormones and thyroid-stimulating hormones, such as thyroid stimulating hormone (TSH) and thyrotrophin, from the anterior pituitary while inhibiting the release of dopamine from the midbrain, norepinephrine, TRH and corticotrophin-releasing hormone in the brain. **Pancreas:** In the pancreas, somatostatin reduces the secretion of glucagon and insulin as well as bicarbonate ions and other enzymes. **Thyroid gland:** Somatosatin reduces secretion of T3, T4, and calcitonin. Somatostatin regulates the thyroid function by reducing basal TSH release. **Gastrointestinal tract:** It attenuates the release of most gastrointestinal hormones such as gastrin, secretin, motilin, gastric acid, enteroglucagon, cholecystokinin (CCK), vasoactive intestinal peptide (VIP), gastric inhibitory polypeptide (GIP), intrinsic factor, pepsin, neurotensin, as well as bile secretion and colonic fluid secretion. **Adrenal gland:** It inhibits angiotensin II-stimulated aldosterone secretion and acetylcholine-induced medullary catecholamine secretion. **Eye/retina:** Somatostatin inhibits the production of vascular endothelial growth factor. **Inflammatory cells and sensory nerves:** The expression of somatostatin has been found in inflammatory cells such as lymphocytes, monocytes, macrophages and endothelial cells to act as an autocrine or paracrine regulator in local immune responses. Findings suggest that somatostatin may play a role in exerting local and systemic anti-inflammatory and antinociceptive effects. On primary afferent neurons, somatostatin reduces the responses to thermal stimulation in C-mechanoheat sensitive fibers in a dose-dependent fashion and reduces the responses of C-mechanoheat fibers to bradykinin-induced excitation and sensitization to heat. Somatostatin is reported to elicit an analgesic effect when applied intrathecally; there is evidence supporting that similar effects may occur when systemically used to treat endocrine disorders. Somatostatin is thought to reduce bleeding from esophageal varices by causing splanchnic vasoconstriction. Somatostatin elicits anti-neoplastic actions on various tumours via direct or indirect effects, or a combination of both.


5.2 MeSH Pharmacological Classification

Hormones

Chemical substances having a specific regulatory effect on the activity of a certain organ or organs. The term was originally applied to substances secreted by various ENDOCRINE GLANDS and transported in the bloodstream to the target organs. It is sometimes extended to include those substances that are not produced by the endocrine glands but that have similar effects. (See all compounds classified as Hormones.)


5.3 ATC Code

H - Systemic hormonal preparations, excl. sex hormones and insulins

H01 - Pituitary and hypothalamic hormones and analogues

H01C - Hypothalamic hormones

H01CB - Somatostatin and analogues

H01CB01 - Somatostatin


5.4 Absorption, Distribution and Excretion

Absorption

This pharmacokinetic data is irrelevant.


Route of Elimination

As a polypeptide chain, somatostatin is primarily eliminated via metabolism by peptidase enzymes.


Volume of Distribution

This pharmacokinetic data is irrelevant.


Clearance

Following intravenous administration of 3H-labeld endogenous somatostatin, the total body clearance was approximately 50 mL/min. In man, the value was calculated to be as high as 3000 mL/minutes, which is greatly exceeds the hepatic blood flow. This suggests that rapid enzymatic breakdown in the circulation and other tissues serves as a critical route of elimination.


5.5 Metabolism/Metabolites

Somatostatin is rapidly degraded by peptidase enzymes present in cells and plasma.


5.6 Biological Half-Life

The half-life of endogenous somatostatin is 1-3 minutes due to rapid degradation by peptidase enzymes present in the plasma and tissues.


5.7 Mechanism of Action

Somatostatin binds to 5 subtypes of somatostatin receptors (SSTRs), which are all Gi-protein-coupled transmembrane receptors that inhibits adenylyl cyclase upon activation. By inhibiting intracellular cyclic AMP and Ca2+ and by a receptor-linked distal effect on exocytosis, SSTRs block cell secretion. The common pathway shared by the receptors involve the activation of phosphotyrosine phosphatase (PTP), and modulation of mitogen-activated protein kinase (MAPK). With the exception of SSTR3, activation of SSTRs lead to activation of voltage-gated potassium channels accompanied by increased K+ currents. This result in membrane hyperpolarization and inhibits depolarization-induced Ca2+ influx through voltage-sensitive Ca2+ channels. Depending on the receptor subtype, signalling cascades involve activation of other downstream targets such as Na+/H+ exchanger, Rho GTPase, and nitric oxide synthase (NOS). SSTRs 1 to 4 bind both somatostatin isoforms with equal nanomolar binding affinity whereas SSTR5 exhibits a 5- to 10-fold higher binding affinity for SST-28. **Effects of SSTR1:** Upon biding of somatostatin and activation, SSTR1 mediates an antisecretory effect on growth hormone, prolactin and calcitonin. **Effects of SSTR2:** SSTR2 subtype dominates in endocrine tissues. By binding to SST2 receptors, somatostatin exerts paracrine inhibitory actions on gastrin release from G cells, histamine release from ECL cells, and directly on parietal cell acid output. SSTR2 receptor signalling cascades also inhibit the secretion of growth hormone and that of adrenocorticotropin, glucagon, insulin, and interferon-. **Effects of SSTR3:** Activation of these receptors lead to reduction in cell proliferation. SSTR3 triggers PTP-dependent cell apoptosis accompanied by activation of p53 and the pro-apoptotic protein Bax. A study of the matrigel sponge assay suggests that through SSTR3-mediated inhibition of both NOS and MAPK activities may lead to the antitumor effects of somatostatin in inhibiting tumor angiogenesis. **Effects of SSTR4:** The functions of SSTR4 remain largely unknown. **Effects of SSTR5:** Like SSTR2, SSTR5 subtype also predominates in endocrine tissues. Upon activation, SSTR5 signalling cascades exert an inhibitory action on growth hormone, adrenocorticotropin, insulin, and glucagon-like peptide-1 as well as the secretion of amylase. The presence of somatostatin receptors has been identified in most neuroendocrine tumours, endocrine gastroenteropancreatic (GEP) tumors, paragangliomas, pheochromocytomas, medullary thyroid carcinomas (MTC) and small cell lung carcinomas. The antitumor effects of somatostatin were also effective in various malignant lymphomas and breast tumours. Gastrointestinal hormones, such as gastrin, secretin, and cholecystokinin (CCK), as well as growth hormones and growth factors are thought to be elevated in gastrointestinal tract and neuroendocrine tumours and are inhibited by somatostatin. _In vitro_, somatostatin inhibited epidermal growth factor (EGF)-induced DNA synthesis and replication following which suggest that somatostatin may have direct anti-proliferative effects via SSTR signalling. Acromegaly is characterized as the endocrine disorder caused by a functioning tumour of cells that secrete growth hormone from the anterior pituitary. Somatostatin analogue therapies serve to normalize the elevated levels of GH and insulin-like growth factor 1 (IGF-1) and attenuate tumour growth. In the vascular system this likely produces vasoconstriction by inhibiting adenylate cyclase leading to a lowering the concentration of cyclic adenosine monophosphate in the endothelial cells which ultimately blocks vasodilation through this pathway. This vasoconstriction is though the be responsible for reducing blood flow to the esophageal tissues and so reduces bleeding from esophageal varices. Somatostatin mediates an analgesic activity by reducing vascular and nociceptive components of inflammation. Studies indicate that somatostatin may be present in nociceptive DRG neurons with C-fibers and primary afferent neurons to inhibit the release of transmitters at the presynaptic junctions of the sensory-efferent nerve terminals. Exogenous somatostatin has shown to inhibit the release of Substance P from central and peripheral nerve ending.