Somatostatin sst4 Ligands: Chemistry and Pharmacology

Crider, A. Michael; Witt, K.

doi:10.2174/138955707780059880

Cited by 16 publications

(6 citation statements)

References 57 publications

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“…In phase II clinical trials for the treatment of acromegaly, veldoreotide proved to be effective when administered by s.c. bolus or s.c. infusion (ClinicalTrials.gov NCT02235987 and NCT02217800). TT-232 is a stable cyclic heptapeptide with partial activity at SST 4 that also binds to SST 1 ( Crider and Witt, 2007 ). Compound J-2156, a nonpeptide agonist displaying high selectivity and high affinity for SST 4 ( Fig.…”

Section: Somatostatin Receptormentioning

confidence: 99%

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International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature

et al. 2018

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Somatostatin, also known as somatotropin-release inhibitory factor, is a cyclopeptide that exerts potent inhibitory actions on hormone secretion and neuronal excitability. Its physiologic functions are mediated by five G protein–coupled receptors (GPCRs) called somatostatin receptor (SST)1–5. These five receptors share common structural features and signaling mechanisms but differ in their cellular and subcellular localization and mode of regulation. SST2 and SST5 receptors have evolved as primary targets for pharmacological treatment of pituitary adenomas and neuroendocrine tumors. In addition, SST2 is a prototypical GPCR for the development of peptide-based radiopharmaceuticals for diagnostic and therapeutic interventions. This review article summarizes findings published in the last 25 years on the physiology, pharmacology, and clinical applications related to SSTs. We also discuss potential future developments and propose a new nomenclature.

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Section: Somatostatin Receptormentioning

confidence: 99%

“…Both TT-232 and J-2156 exhibited anti-inflammatory and antinociceptive effects after i.p. administration in rodents ( Crider and Witt, 2007 ). NNC26-9100 is the lead compound of another structurally distinct class of highly selective SST 4 agonists ( Liu et al, 1998 ).…”

Section: Somatostatin Receptormentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature

et al. 2018

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“…Several hepta-and octapeptide somatostatin analogs, such as TT-232 [24,25], were shown to induce anti-inflammatory and antinociceptive effects [13,[26][27][28][29], predominantly via sst4 activation [13,28,30]. Despite the great effectivity of the peptide agonists in preclinical models, they are not appropriate for oral application that would be preferred for chronic treatment.…”

Section: Introductionmentioning

confidence: 99%

“…We provided several lines of evidence that the broad anti-inflammatory, antinociceptive and anti-hyperalgesic effects of somatostatin are mediated by the sst 4 receptor without influencing endocrine functions [1,4,[14][15][16][17]. Therefore, the sst 4 receptor has become a well-established novel drug target and the development of sst 4 agonists has recently been included in the scope of several pharmaceutical companies [13,[18][19][20][21][22][23].Several hepta-and octapeptide somatostatin analogs, such as 25], were shown to induce anti-inflammatory and antinociceptive effects [13,[26][27][28][29], predominantly via sst 4 activation [13,28,30]. Despite the great effectivity of the peptide agonists in preclinical models, they are not appropriate for oral application that would be preferred for chronic treatment.…”

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confidence: 99%

Novel Drug-Like Somatostatin Receptor 4 Agonists are Potential Analgesics for Neuropathic Pain

Kántás

Börzsei

Szöke

et al. 2019

IJMS

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Somatostatin released from the capsaicin-sensitive sensory nerves mediates analgesic and anti-inflammatory effects via the somatostatin sst 4 receptor without endocrine actions. Therefore, sst 4 is considered to be a novel target for drug development in pain including chronic neuropathy, which is an emerging unmet medical need. Here, we examined the in silico binding, the sst 4 -linked G-protein activation on stable receptor expressing cells (1 nM to 10 µM), and the effects of our novel pyrrolo-pyrimidine molecules in mouse inflammatory and neuropathic pain models. All four of the tested compounds (C1-C4) bind to the same binding site of the sst 4 receptor with similar interaction energy to high-affinity reference sst 4 agonists, and they all induce G-protein activation. C1 is the more efficacious (γ-GTP-binding: 218.2% ± 36.5%) and most potent (EC 50 : 37 nM) ligand. In vivo testing of the actions of orally administered C1 and C2 (500 µg/kg) showed that only C1 decreased the resiniferatoxin-induced acute neurogenic inflammatory thermal allodynia and mechanical hyperalgesia significantly. Meanwhile, both of them remarkably reduced partial sciatic nerve ligation-induced chronic neuropathic mechanical hyperalgesia after a single oral administration of the 500 µg/kg dose. These orally active novel sst 4 agonists exert potent anti-hyperalgesic effect in a chronic neuropathy model, and therefore, they can open promising drug developmental perspectives. strongly limited by its diverse effects and rapid degradation and consequently short elimination half-life (<3 min) [9]. However, stable and potent synthetic analogs could be potential analgesic candidates.A wide range of somatostatin effects are mediated via five inhibitory G-protein-coupled receptor subtypes (GPCRs) [10,11] which have seven transmembrane domains (TMDs). They are divided into two classes on the basis of their phylogeny, structural homologies and pharmacological properties. The somatotropin release-inhibiting factor 1 (SRIF1) receptor class involves sst 2 , sst 3 and sst 5 mediating important endocrine actions of somatostatin (e.g., inhibition of growth hormone, insulin, glucagon secretion), and the SRIF2 class includes sst 1 and sst 4 [10]. It is well known that sst 4 receptor is present in the dorsal root ganglia cells and spinal cord dorsal horn, and can also mediate analgesic effects along with the δ-opioid receptor [12,13]. We provided several lines of evidence that the broad anti-inflammatory, antinociceptive and anti-hyperalgesic effects of somatostatin are mediated by the sst 4 receptor without influencing endocrine functions [1,4,[14][15][16][17]. Therefore, the sst 4 receptor has become a well-established novel drug target and the development of sst 4 agonists has recently been included in the scope of several pharmaceutical companies [13,[18][19][20][21][22][23].Several hepta-and octapeptide somatostatin analogs, such as 25], were shown to induce anti-inflammatory and antinociceptive effects [13,[26][27][28][29], predominantly via sst 4 activ...

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“…Hence, it is important to identify new targets for development of novel analgesic agents with improved efficacy and tolerability for alleviation of BCIBP. One such target is the somatostatin receptor type 4 (SST4 receptor) (Crider and Witt, 2007 ; Somvanshi and Kumar, 2014 ; Abdel-Magid, 2015 ). J-2156 [(1′S,2S)-4amino-N-(1′-carbamoyl-2′-phenylethyl)-2-(4″-methyl-1″-naphthalenesulfonylamino)butanamide] is an agonist that binds with nanomolar affinity to the human SST4 receptor and that has more than 300-fold selectivity compared with other somatostatin receptors (Engström et al, 2005 ).…”

Section: Introductionmentioning

confidence: 99%

The Somatostatin Receptor-4 Agonist J-2156 Alleviates Mechanical Hypersensitivity in a Rat Model of Breast Cancer Induced Bone Pain

et al. 2018

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In the majority of patients with breast cancer in the advanced stages, skeletal metastases are common, which may cause excruciating pain. Currently available drug treatments for relief of breast cancer-induced bone pain (BCIBP) include non-steroidal anti-inflammatory drugs and strong opioid analgesics along with inhibitors of osteoclast activity such as bisphosphonates and monoclonal antibodies such as denosumab. However, these medications often lack efficacy and/or they may produce serious dose-limiting side effects. In the present study, we show that J-2156, a somatostatin receptor type 4 (SST4 receptor) selective agonist, reverses pain-like behaviors in a rat model of BCIBP induced by unilateral intra-tibial injection of Walker 256 breast cancer cells. Following intraperitoneal administration, the ED50 of J-2156 for the relief of mechanical allodynia and mechanical hyperalgesia in the ipsilateral hindpaws was 3.7 and 8.0 mg/kg, respectively. Importantly, the vast majority of somatosensory neurons in the dorsal root ganglia including small diameter C-fibers and medium-large diameter fibers, that play a crucial role in cancer pain hypersensitivities, expressed the SST4 receptor. J-2156 mediated pain relief in BCIBP-rats was confirmed by observations of a reduction in the levels of phosphorylated extracellular signal-regulated kinase (pERK), a protein essential for central sensitization and persistent pain, in the spinal dorsal horn. Our results demonstrate the potential of the SST4 receptor as a pharmacological target for relief of BCIBP and we anticipate the present work to be a starting point for further mechanism-based studies.

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Somatostatin sst4 Ligands: Chemistry and Pharmacology

Cited by 16 publications

References 57 publications

International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature

International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature

Novel Drug-Like Somatostatin Receptor 4 Agonists are Potential Analgesics for Neuropathic Pain

The Somatostatin Receptor-4 Agonist J-2156 Alleviates Mechanical Hypersensitivity in a Rat Model of Breast Cancer Induced Bone Pain

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