The somatostatin receptor 4 agonist J-2156 reduces mechanosensitivity of peripheral nerve afferents and spinal neurons in an inflammatory pain model

Schuelert, Niklas; Just, Stefan; Kuelzer, Raimund; Corradini, Laura; Gorham, Louise; Doods, Henri

doi:10.1016/j.ejphar.2014.11.003

Cited by 28 publications

(45 citation statements)

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“…Therefore, small molecule nonpeptide analogs were synthesized for drug developmental purposes. J-2156 is a 1naphthalenesulfonylamino-peptidomimetic, which is a sst4 "superagonist" [31], having potent antiinflammatory, analgesic and antidepressant actions [15,[32][33][34][35].…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, small molecule nonpeptide analogs were synthesized for drug developmental purposes. J-2156 is a 1-naphthalenesulfonylamino-peptidomimetic, which is a sst 4 "superagonist" [31], having potent anti-inflammatory, analgesic and antidepressant actions [15,[32][33][34][35].NNC26-9100 and L-803,087 are compounds of other structurally distinct classes of highly selective small molecule sst 4 agonists [36,37], and they are widely used as reference materials [9]. In previous studies, NNC26-9100 and L-803,087 were effective in models of different neurological diseases, such as Alzheimer's disease and epilepsy [38,39], but they are not suitable for oral administration, which presumably contributed to them not being candidates for drug development.Here, we report the sst 4 receptor binding and activation of novel small molecule pyrrolo-pyrimidine molecules (Compound 1 = C1, Compound 2 = C2, Compound 3 = C3, Compound4 = C4) ( Figure 1) [40], as well as their effects in an acute neurogenic inflammatory hyperalgesia model mimicking peripheral and central sensitization mechanisms and in a translationally relevant chronic neuropathic pain model.…”

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confidence: 99%

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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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Section: Introductionmentioning

confidence: 99%

mentioning

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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“…We provided strong evidence that its activation exerts analgesic and anti‐inflammatory effects in several models by directly inhibiting primary nociceptive nerve endings and decreasing proinflammatory neuropeptide release, as well as acting on vascular endothelial, inflammatory, and immune cells. Stable, sst 4 ‐selective agonists are likely to be suitable for drug development, but so far only preclinical evidence has been provided and candidates have not entered the clinical phase …”

Section: Novel Targets With Anti‐inflammatory And/or Analgesic Potentmentioning

confidence: 99%

Challenges to develop novel anti‐inflammatory and analgesic drugs

Botz

Bölcskei

Helyes

2016

WIREs Nanomed Nanobiotechnol

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Chronic inflammatory diseases and persistent pain of different origin represent common medical, social, and economic burden, and their pharmacotherapy is still an unresolved issue. Therefore, there is a great and urgent need to develop anti-inflammatory and analgesic agents with novel mechanisms of action, but it is a very challenging task. The main problem is the relatively large translational gap between the preclinical experimental data and the clinical results due to characteristics of the models, difficulties with the investigational techniques particularly for pain, as well as species differences in the mechanisms. We summarize here the current state-of-the-art medication and related ongoing strategies, and the novel targets with lead molecules under clinical development. The first members of the gold-standard categories, such as nonsteroidal anti-inflammatory drugs, glucocorticoids, and opioids, were introduced decades ago, and since then very few drugs with novel mechanisms of action have been successfully taken to the clinics despite considerable development efforts. Several biologics targeting different key molecules have provided breakthrough in some autoimmune/inflammatory diseases, but they are expensive, only parenterally available, their long-term side effects often limit their administration, and they do not effectively reduce pain. Some kinase inhibitors and phosphodiesterase-4 blockers have recently been introduced as new directions. There are in fact some promising novel approaches at different clinical stages of drug development focusing on transient receptor potential vanilloid 1/ankyrin 1 channel antagonism, inhibition of voltage-gated sodium/calcium channels, several enzymes (kinases, semicarbazide-sensitive amine oxidases, and matrix metalloproteinases), cytokines/chemokines, transcription factors, nerve growth factor, and modulation of several G protein-coupled receptors (cannabinoids, purinoceptors, and neuropeptides). WIREs Nanomed Nanobiotechnol 2017, 9:e1427. doi: 10.1002/wnan.1427 For further resources related to this article, please visit the WIREs website.

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“…has high potency and a low propensity to cause receptor desensitisation (Engström et al, 2006, Engstrom et al, 2005. Additionally, in work by others, J-2156 has been shown to induce pain relief in animal models of both inflammatory and neuropathic pain (Sándor et al, 2006, Schuelert et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…Due to limited permeability of the blood-brain barrier, at the doses tested, J-2156 is considered likely to act on peripheral SST4 receptors, although it is also capable of inhibiting spinal neurons (Schuelert et al, 2015). Peripheral small diameter peptidergic and non-peptidergic C-fibres as well as medium-large diameter fibres including A-and A-β fibres have key roles in the neural signalling of cancer pain (Colvin and Fallon, 2008, Ye et al, 2014c, Mantyh, 2006, Urch et al, 2003, Mao-Ying et al, 2006, Donovan-Rodriguez et al, 2005.…”

Section: Introductionmentioning

confidence: 99%

Establishment, optimization and characterization of a rat model of breast cancer induced bone pain

Shenoy¹

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providing me necessary infrastructure, funds and all the guidance and support required throughout my PhD candidature. I will always remain very thankful to Dr Vetter who chose me as a PhD student and provided me with a life-changing opportunity of studying in Australia. My PhD project work was conducted in Professor Smith's laboratory at Centre for Integrated Preclinical Drug Development (CIPDD/TetraQ) (Centre for Clinical Research, Faculty of Medicine). I have seen Professor Smith as a strict mentor, yet certainly one of the kindest, most compassionate and revered persons I have ever met. These years of my professional associations with Professor Smith have left deep positive imprints on me, and I will cherish them for the rest of my life. Without Professor Smith's solid support throughout my candidature, I would have never seen this day of my life. Words will never be enough to express my feelings, but all I can very genuinenly say is that I have experienced the Almighty God in Professor Smith. I am grateful to Dr Kuo for his persistent support in my candidature.

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The somatostatin receptor 4 agonist J-2156 reduces mechanosensitivity of peripheral nerve afferents and spinal neurons in an inflammatory pain model

Cited by 28 publications

References 50 publications

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

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

Challenges to develop novel anti‐inflammatory and analgesic drugs

Establishment, optimization and characterization of a rat model of breast cancer induced bone pain

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