J-2156, a somatostatin receptor type 4 agonist, alleviates mechanical hyperalgesia in a rat model of chronic low back pain

Park, Thomas S.W.; Khan, Nemat; Kuo, Andy; Nicholson, Janet R.; Corradini, Laura; Smith, M. T.

doi:10.1016/j.biopha.2019.109056

Cited by 9 publications

(27 citation statements)

References 68 publications

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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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“…bolus doses of the SST 4 receptor agonist, J‐2156 at 10 and 30 mg/kg, significantly alleviated secondary but not primary hyperalgesia. This finding is somewhat puzzling as our recent work in the moderate to severe LBP‐10X rat model of cLBP, 15 showed that J‐2156 significantly evoked dose‐dependent relief of both primary and secondary hyperalgesia in these animals. By comparing our J‐2156 response vs time curves in the LBP‐5X model with those for the LBP‐10X model, it is clear that in the former model, the peak effect of J‐2156 occurred at 60–90 minutes post‐dosing and the duration of action was >3 hours whereas in the latter model, the peak effect was at 30 minutes post‐dosing and the duration of action was approximately 2 hours.…”

Section: Discussionmentioning

confidence: 90%

“…Additionally, the SST 4 receptor agonist, TT 232 alleviated mechanical allodynia in the hindpaws of rodent models of painful diabetic neuropathy 30 . From our laboratory, we have shown that J‐2156 evoked dose‐dependent pain relief in a rat model of breast cancer‐induced bone pain 14 and dose‐dependent relief of mechanical hypersensitivity in the lumbar axial deep tissues in a rat model of moderate to severe mechanical low back pain (10X) 15 . Clinically, intra‐articular injection of somatostatin into the osteoarthritic knee in patients over a 4‐week period resulted in significant improvement in knee joint pain and functionality 31 .…”

Section: Discussionmentioning

confidence: 99%

“…This unmet medical need is driving research aimed at discovery of new molecules that are efficacious and well‐tolerated. Of interest, J‐2156, an investigational small molecule somatostatin type 4 (SST4) receptor agonist has been shown by our laboratory to alleviate prostate cancer‐induced bone pain in rats 14 as well as chronic mechanical LBP in a moderately severe (LBP‐10X) rat model 15 . However, its efficacy in a mild to moderate rat model of chronic mechanical LBP remains to be assessed.…”

Section: Introductionmentioning

confidence: 99%

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Assessment of the anti‐hyperalgesic efficacy of J‐2156, relative to clinically available analgesic/adjuvant agents in a rat model of mild to moderate chronic mechanical low back pain (LBP)

Kuo

Lourdesamy

Nicholson

et al. 2020

Clin Exp Pharma Physio

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Chronic mechanical low back pain (cLBP) is a leading cause of disability and a major socio‐economic burden internationally. The lifetime prevalence of non‐specific LBP is approximately 84%, with the prevalence of cLBP at about 23%. Clinically available analgesic/adjuvant medications often provide inadequate pain relief in patients experiencing cLBP. Hence, the urgency for discovery of effective and better tolerated medications. Fourteen days after the induction of five shallow annular punctures (5X) in the lumbar intervertebral discs at L4/L5 and L5/L6 in male Sprague‐Dawley rats, mechanical hyperalgesia was fully developed in the lumbar axial deep tissues at L4/L5 (primary) and L1 (secondary). Importantly, mechanical allodynia in the hindpaws was absent. From day 28, we assessed the face validity of our mild to moderate LBP‐5X rat model using four clinically available analgesic/adjuvant drugs, namely gabapentin, morphine, meloxicam and amitriptyline relative to vehicle. Additionally, the anti‐hyperalgesic effects of J‐2156, a highly selective small molecule somatostatin type 4 receptor agonist was assessed. Single i.p. bolus doses of gabapentin and meloxicam at the highest doses tested (100 and 30 mg/kg, respectively) alleviated secondary hyperalgesia (L1) but not primary hyperalgesia (L4/5). Morphine at 1 mg/kg alleviated both primary and secondary hyperalgesia in these tissues, whereas amitriptyline at the doses tested, lacked efficacy. These findings attest to the face validity of our model. J‐2156 at 10 and 30 mg/kg alleviated secondary hyperalgesia in the lumbar axial deep tissues at L1 with a non‐significant trend for relief of primary hyperalgesia in the corresponding tissues at L4/L5 in these animals.

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Drug effects on neuropeptides and their receptors: Big hopes but moderate success in the treatment of chronic pain

Borbély,

Pethő

2024

Current Opinion in Pharmacology

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J-2156, a somatostatin receptor type 4 agonist, alleviates mechanical hyperalgesia in a rat model of chronic low back pain

Cited by 9 publications

References 68 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

Assessment of the anti‐hyperalgesic efficacy of J‐2156, relative to clinically available analgesic/adjuvant agents in a rat model of mild to moderate chronic mechanical low back pain (LBP)

Drug effects on neuropeptides and their receptors: Big hopes but moderate success in the treatment of chronic pain

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