Somatostatin Receptors

Somatostatin (somatotropin release-inhibiting factor, SRIF) is a cyclic peptide widely expressed throughout the CNS, endocrine tissues and gastrointestinal tract. The 14 amino acid peptide, somatostatin (SRIF-14), was first identified and isolated from ovine hypothalamic extracts as a potent inhibitor of growth hormone release from the pituitary. Subsequently, a longer N-terminally extended form (SRIF-28) was identified. SRIF exerts a wide range of biological actions, including inhibition of secretion of growth hormone, insulin, glucagon and gastrin as well as other hormones secreted by the pituitary and gastrointestinal tract. Somatostatin also acts as a neuromodulator in the CNS and shows anti-proliferative effect on a wide range of cancer cells. A rat neuropeptide, named cortistatin (CST), with strong homology to SRIF has also been cloned. Depending on the species, CST is a tetradecapeptide, sharing up to 11 amino acids with SRIF. The human homolog of CST appears to be a heptadecapeptide (CST-17). By analogy with SRIF, there may also be a larger isoform of CST, i.e. CST-29. Although various physiological parameters, including transitions between sleep phases, consolidation of short- and long-term memory and locomotor activity, respond in an apparently transmitter-specific manner to SRIF and CST, the latter is an endogenous ligand at SRIF receptors, with nanomolar affinity for each subtype. The existence of specific CST receptors has not been demonstrated so far, although it was suggested that MGRX2 may play such a role.

SRIF and CST act via a family of G protein-coupled receptors, of which five subtypes (sst1-sst5) have been cloned and characterized from various species. Sequence homology is 39-57% among the five subtypes, each being highly conserved across species. Based on structural and operational features, they can be divided into two groups: SRIF-1 includes sst2, sst3 and sst5 receptors while SRIF-2 consists of sst1 and sst4 receptors, distinguished by high affinity of cyclic peptides such as octreotide (SMS-201-995), seglitide (MK-678) and lanreotide (BIM-23014) for the SRIF-1 group.

Molecular biological techniques and subtype selective antibodies have been used to determine the distribution of the sst1-sst5 gene transcripts and receptor protein in brain and periphery. Selective peptidic agonists at sst1 (CH-275) and sst4 receptors (NNC 26-9100) have been described, as has an sst3 receptor antagonist (sst3-ODN-8). However, the use of peptides for in vivo experiments is limited by pharmacokinetic constraints that may be addressed by the recent description of non-peptide agonists selective for each of the five somatostatin receptors. Further, non-peptide antagonists such as SRA880 (sst1 selective), ACQ090 (sst3 selective) and sst4 selective β peptide agonists which all show adequate stability and bioavailability have been described more recently.

Studies utilizing subtype selective SRIF analogs in both in vivo and in vitro experiments demonstrate that sst2 receptors are the major player in the SRIF receptor family with broad inhibitory effects on the endocrine secretion, e.g. growth hormone, insulin, glucagon, gastrin, cholecystokinin, vasoactive intestinal peptide and secretin, as well as the exocrine secretion, e.g. gastric acid, intestinal fluid and pancreatic enzymes. Sst2 receptors also seem to play a major role in various forms of gastro-enteropancreatic cancers, in epilepsy and pain. The sst1 receptor may function as an autoreceptor at least in basal ganglia and the eye. Sst3 receptors are enigmatically localized to neuronal cilia, and sst3 antagonists have marked behavioral effects. Sst4 receptors are highly expressed in the lung, but their role remains to be defined, although in the mouse they modulate epileptic activity. Sst5 receptors mediate inhibition of insulin release from the pancreatic β-cells in addition to regulating growth hormone release.

 

The Table below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.

 

Currently Accepted Namea sst1 sst2 sst3 sst4 sst5
Alternate Names SRIF-2 SRIF-1 SRIF-1 SRIF-2 SRIF-1
Structural Information 391 aa (human) 369 aa (human) 418 aa (human) 388 aa (human) 364 aa (human)
Selective Agonists CH-275
L-797,591
MK-678 (Seglitide)
BIM-23027 (B0434)
L-054,522
L-779,976
L-796,778 NNC 26-9100
L-803,087
L-817,818
Selective Antagonists NVP-SRA880 Cyanamid-154806 (C2490) sst3-ODN-8
NVP-ACQ090
Not Known
BIM-23056 (B4310)
Signal Transduction Mechanisms Gi (cAMP modulation) Gi (cAMP modulation)
PLC/PKC/ MAPKinase
Gi (cAMP modulation)
PLC/PKC/ MAPKinase
Gi (cAMP modulation) Gi (cAMP modulation)
PLC
PKC
Calcium
Radioligands of Choice [125I]-[Tyr25]-SRIF28 [125I]-[Tyr25]-SRIF28 [125I]-[Tyr25]-SRIF28 [125I]-[Tyr25]-SRIF28 [125I]-[Tyr25]-SRIF28
Tissue Expression Brain, cortex, eye, hypothalamus Brain, pancreas, pituitary, GI tract Neuronal cilia, lymphocytes Brain, hippocampus, lung Brain, pituitary, vascular smooth muscle
Physiological Function Autoreceptor Inhibition of hormone release, inhibition of tumor growth Apoptosis, tumor cell growth inhibition Tumors Inhibition of insulin release, tumor growth
Disease Relevance Not known Acromegaly, GEP tumors, pain, GI tract disorders, epilepsy Sarcomas Not known Acromegaly

 

Abbreviations

BIM-23027: c[N-methyl-Ala-Tyr-D-Trp-Lys-Abu-Phe]
BIM-23056: D-Phe-Phe-Tyr-D-Trp-Lys-Val-Phe-D-Nal-NH2
CH-275: des-AA1,2,5(D-Trp8,Iamp9)-SRIF
Cyanamid-154806: AC-4-NO2-Phe-c[D-Cys-Tyr-D-Trp-Lys-Thr-Cys]-D-Tyr-NH2
GEP: Gastro-enteropancreatic
GI: Gastrointestinal
MK-678 (Seglitide): c[N-Methyl-Ala-Tyr-D-Trp-Lys-Val-Phe]
L-797,591: (2R)-N-(6-Amino-2,2,4-trimethylhexyl)-3-(1-naphthyl)-2-({[(2-phenylethyl)(2-pyridin-2-ylethyl)amino]carbonyl}amino)propanamide
L-054,522: tert-Butyl (bS)-b-methyl-N-{[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]carbonyl}-D-tryptophyl-L-lysinate
L-779,976: (bS)-N-{[3-(Aminomethyl)cyclohexyl]methyl}-b-methyl-N-{[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]carbonyl}-D-tryptophamide
L-796,778: Methyl (2S)-6-amino-2-[((2R)-2-{[({(1S)-1-benzyl-2-[(4-nitrophenyl)amino]-2-oxoethyl}amino)carbonyl]amino}hexanoyl)amino]hexanoate
L-803,087: Methyl (2S)-5-{[amino(imino)methyl]amino}-2-{[4-(5,7-difluoro-2-phenyl-1H-indol-3-yl)butanoyl]amino}pentanoate or methyl N2-[4-(5,7-difluoro-2-phenyl-1H-indol-3-yl)butanoyl]-L-argininate
L-817,818: (2R)-2-Aminopropyl N2-{[2-(2-naphthyl)-1H-benzo[g]indol-3-yl]acetyl}-L-lysinat
NNC 26-9100: I-[3-[N-(5-Bromopyridin-2-yl)-N-(3,4-dichlorobenzyl)aminopropyl]-3-[3-(1H-imidazol-1-yl)propyl]-thiourea
NVP-ACQ090: [4-(3,4-Difluoro-phenyl)-piperazin-1-yl]-{(4S,4aS,8aR)-2-[(S)-3-(6-methoxy-pyridin-3-yl)-2-methyl-propyl]-decahydro-isoquinolin-4-yl}-methanone
NVP-SRA880: [3R,4aR,10aR]-1,2,3,4,4a,5,10,10a-Octahydro-6-methoxy-1-methyl-benz[g] quinoline-3-carboxylic-acid-4-(4-nitro-phenyl)-piperazine-amide, hydrogen malonate
sst3-ODN-8: Carbamoyl-des-AA1,2,4,5,12,13[D-Cys3,D-Arg18(Me,2-naphthoyl)]-SRIF
[125I]-[Tyr25]-SRIF28: 3-[125I]iodotyrosyl25-SRIF-(Leu8,D-Trp22,Tyr25)

 

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References