Challenges to develop novel anti‐inflammatory and analgesic drugs

Botz, Bálint; Bölcskei, Kata; Helyes, Zsuzsanna

doi:10.1002/wnan.1427

Cited by 23 publications

(20 citation statements)

References 263 publications

(454 reference statements)

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“…The importance of these results is highlighted by the fact that neuropathic pain is very resistant to conventional analgesics: the effect of opioids and NSAIDs is almost absent in neuropathic conditions [27,[57][58][59]. Adjuvant analgesics (e.g., antiepileptics, antidepressants) might have limited effects in certain cases, but they could exert several serious adverse effects [60].…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…There is a strong proof-of-concept that SST 4 is a unique novel drug target for neuropathic pain, which could be also valuable to treat depression as a common comorbidity [ 8 , 9 , 22 , 23 , 24 ]. Non-peptide SST 4 agonists have recently come in the focus of interest of pharma industry [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

Characterization of Neurons Expressing the Novel Analgesic Drug Target Somatostatin Receptor 4 in Mouse and Human Brains

Kecskés

Pohóczky

Kecskés

et al. 2020

IJMS

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Somatostatin is an important mood and pain-regulating neuropeptide, which exerts analgesic, anti-inflammatory, and antidepressant effects via its Gi protein-coupled receptor subtype 4 (SST4) without endocrine actions. SST4 is suggested to be a unique novel drug target for chronic neuropathic pain, and depression, as a common comorbidity. However, its neuronal expression and cellular mechanism are poorly understood. Therefore, our goals were (i) to elucidate the expression pattern of Sstr4/SSTR4 mRNA, (ii) to characterize neurochemically, and (iii) electrophysiologically the Sstr4/SSTR4-expressing neuronal populations in the mouse and human brains. Here, we describe SST4 expression pattern in the nuclei of the mouse nociceptive and anti-nociceptive pathways as well as in human brain regions, and provide neurochemical and electrophysiological characterization of the SST4-expressing neurons. Intense or moderate SST4 expression was demonstrated predominantly in glutamatergic neurons in the major components of the pain matrix mostly also involved in mood regulation. The SST4 agonist J-2156 significantly decreased the firing rate of layer V pyramidal neurons by augmenting the depolarization-activated, non-inactivating K+ current (M-current) leading to remarkable inhibition. These are the first translational results explaining the mechanisms of action of SST4 agonists as novel analgesic and antidepressant candidates.

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“…Based on the methodology of purposeful search of NSAIDs an effective method for the synthesis of 6-spirofused 10-R-3-aryl-6,7-dihydro-2H- [1,2,4]triazino [2,3-c] quinazolin-2-ones (a promising class of anti-inflammatory agents) was proposed. Structural features of the synthesized compounds, as well as their 1 H, 13 C NMR spectroscopy and mass spectrometry data were discussed.…”

Section: соNclusionsmentioning

confidence: 99%

“…Advances in molecular biology in the last decades allowed to characterize every stage of this process and made it possible to form a number of approaches of the creation of this drug group. 3,4 Thus, the main trends in the creation of innovational drugs include the development of С5a receptor antagonists, inhibitors of interleukin converting enzyme and tumor necrosis factor inhibitors, p38 MAP kinase inhibitors, inhibitors of matrix metalloproteinase, etc. Undoubtedly, the mentioned strategy with the use of de novo methodology (molecular docking) and X-ray analysis of the macromolecules active-site has significantly changed the direction of the synthetic work aimed at creating the drugs for correcting the inflammation.…”

Section: Introductionmentioning

confidence: 99%

“…So, purposeful search of selective anti-inflammatory agents among original derivatives of 10-R-3-aryl-6,7-dihydro-2H- [1,2,4]triazino [2,3-c]quinazolin-2-ones of spirofused cyclic frameworks was the aim of this work. That is based on rational design, namely structural similarity to a number of innovative and well-known drugs and forecasting the likely biological effects (COX inhibitors) using methods of computer modeling and in vivo tests.…”

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis and Anti-inflammatory Activity of Derivatives 10-R-3-Aryl-6,7-dihydro-2H-[1,2,4] triazino[2,3-c]quinazolin-2-ones of Spiro-fused Cyclic Frameworks

Kolomoets

Voskoboynik

Antypenko

et al. 2017

ACSi

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Present work is devoted to the purposeful search of novel promising anti-inflammatory agents among the insufficiently known 3'-R-10'-R 1 -spiro[hetaryl-3(4),6'-[1,2,4]triazino[2,3-c]quinazolin]-2'(7'H)-ones. The virtual combinatorial library of previously unknown spiro-condensed derivatives of [1,2,4]triazino[2,3-c]quinazolines was formed and promising COX-2 inhibitors were identified by molecular docking method. Potential anti-inflammatory agents were synthesized by [5+1]-cyclocondensation of substituted 3-(2-aminophenyl)-6-R-1,2,4-triazin-5(2H)-ones with heterocyclic ketones. The structures of synthsized compounds were verified by complex of physicochemical methods and spectral characteristics features were discussed. Obtained compounds were studied for anti-inflammatory activity using formalin induced paw edema model and highly active compounds were identified. Conducted SAR-analysis showed that combination of triazino [2,3-c] quinazoline moiety with spiro-condensed fragments is a reasonable approach for creating novel anti-inflammatory agents.

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Challenges to develop novel anti‐inflammatory and analgesic drugs

Cited by 23 publications

References 263 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

Characterization of Neurons Expressing the Novel Analgesic Drug Target Somatostatin Receptor 4 in Mouse and Human Brains

Design, Synthesis and Anti-inflammatory Activity of Derivatives 10-R-3-Aryl-6,7-dihydro-2H-[1,2,4] triazino[2,3-c]quinazolin-2-ones of Spiro-fused Cyclic Frameworks

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