Potential Analgesic Agents Research Articles

Molecular properties prediction and synthesis of new oxadiazole derivatives possessing 3-fluoro-4-methoxyphenyl moiety as potent anti-inflammatory and analgesic agents

A new series of 1,2,4- and 1,3,4-oxadiazole derivatives possessing 3-fluoro-4-methoxyphenyl moiety were efficiently synthesized and characterized by spectroscopic methods and elemental analysis. All the compounds were evaluated in vivo for their anti-inflammatory and analgesic properties, and were found to be low lethal as ascertained by the LD50 test. The present study suggests that three compounds were found to have good anti-inflammatory activity in the carrageenan-induced rat paw edema test, while a fair number of compounds showed significant analgesic activity in the tail flick test. In silico ADME properties of synthesized compounds were also analysed and showed potential to develop as good oral drug candidates.

A one-pot synthesis of indole-appended heterocycles as potent anti-inflammatory, analgesic, and CNS depressant agents

A series of novel 3-[3-(2,5-dichloro-3-thienyl)-substituted-1H-pyrazol-5-yl]-2,5-disubstituted-1H-indoles, 3-[3-(2,5-dichloro-3-thienyl)isoxazol-5-yl]-2,5-disubstituted-1H-indoles, and 4-(2,5-dichloro-3-thienyl)-6-(2,5-disubstituted-1H-indol-3-yl)-substituted pyrimidin-2(5H)-ones were synthesized by means of a one-pot reaction. Structures of all compounds were confirmed by their melting points, elemental analysis, IR, 1H NMR, 13C NMR, and mass spectral data. The novel compounds were evaluated for pharmacological studies and discussed in terms of their structural differences. Among the screened compounds, three show excellent anti-inflammatory activity with maximum inhibition (50.0–59.1 %), i.e. better than the standard drug indomethacin (50.0 %). Four of the compounds revealed highest analgesic potency. In locomotor activity, six compounds exhibited promising results for CNS depressant activity.

3-Methyl-2-phenyl-1-substituted-indole derivatives as indomethacin analogs: design, synthesis and biological evaluation as potential anti-inflammatory and analgesic agents

In a new group of 3-methyl-2-phenyl-1-substituted-indole derivatives (10a–f), the indomethacin analogs were prepared via the Fisher indole synthesis reaction of propiophenone with appropriately substituted phenylhydrazine hydrochloride. This is followed by the insertion of the appropriate benzyl or benzoyl fragment. All the synthesized compounds were evaluated for their anti-inflammatory (in vitro and in vivo) and analgesic activities. The methanesulphonyl derivatives 10d, e and f showed the highest anti-inflammatory (in vitro and in vivo) and analgesic activities. In addition, molecular docking studies were performed on compounds 10a–f and the results were in agreement with that obtained from the in vitro COX inhibition assays. The significant anti-inflammatory and analgesic activities exhibited by 10d and 10e warrant continued preclinical development as potential anti-inflammatory and analgesic agents.

Synthesis and biological evaluation of some novel fused thiazolo[3,2-a]pyrimidines as potential analgesic and anti-inflammatory agents

Synthesis and biological evaluation of some novel fused thiazolo[3,2-a]pyrimidines as potential analgesic and anti-inflammatory agents

Design and Synthesis of Some Enaminonitrile Derivatives of Antipyrine as Potential Novel Anti-Inflammatory and Analgesic Agents

The starting (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)carbon-hydrazonoyl dicyanide (2) was used as a key intermediate for the syntheses of novel acyclic enaminonitriles 3-10. The newly synthesized compounds were characterized by elemental analyses and spectral data (IR, 1H NMR, 13C NMR and mass spectra). The anti-inflammatory activity data indicated that many of tested compounds protected rats from carrageenan-induced inflammation, and tested compounds 3, 4, 9 and 10 were the most potent among tested compounds. The analgesic activity was determined by the hot plate test (central analgesic activity) and acetic acid induced writhing assay. The results revealed that compounds 3, 4, 9, and 10 exhibited significant activity. However, compound 10 proved to have better or equivalent activities in comparison to the reference drug.

SYNTHESIS AND BIOLOGICAL EVALUATION OF SOME NOVEL FUSED THIAZOLO[3,2A]PYRIMIDINES AS POTENTIAL ANALGESIC AND ANTI-INFLAMMATORY AGENTS.

Some novel bicyclic thiazolopyrimidine derivatives bearing various substituents have been synthesized through one-pot three-component method. Structures of the target compounds were confirmed by elemental analysis and spectral data. Some selected members of the newly synthesized compounds were investigated for their analgesic and anti-inflammatory activities and revealed pronounced anti-inflammatory activity greater than that of indomethacin (reference drug).

Morphine Promotes Tumor Angiogenesis and Increases Breast Cancer Progression.

Morphine is considered a highly potent analgesic agent used to relieve suffering of patients with cancer. Several in vitro and in vivo studies showed that morphine also modulates angiogenesis and regulates tumour cell growth. Unfortunately, the results obtained by these studies are still contradictory. In order to better dissect the role of morphine in cancer cell growth and angiogenesis we performed in vitro studies on ER-negative human breast carcinoma cells, MDA.MB231 and in vivo studies on heterotopic mouse model of human triple negative breast cancer, TNBC. We demonstrated that morphine in vitro enhanced the proliferation and inhibited the apoptosis of MDA.MB231 cells. In vivo studies performed on xenograft mouse model of TNBC revealed that tumours of mice treated with morphine were larger than those observed in other groups. Moreover, morphine was able to enhance the neoangiogenesis. Our data showed that morphine at clinical relevant doses promotes angiogenesis and increases breast cancer progression.

PC-FACS

PC-FACS

Synthesis of 6-(4-methanesulphonamidophenyl)-substituted dihydropyridazinone/ phthalazinone derivatives as potent anti-inflammatory and analgesic agents

New 6-(4-methanesulphonamidophenyl)-substituted dihydropyridazinones and their phthalazinone analogues have been synthesized and evaluated for anti-inflammatory and analgesic activities using carrageenan induced paw edema and acetic acid induced writhing models, respectively. Most of the newly synthesized compounds displayed potent anti-inflammatory activity without ulcerogenic side effects. Both pyridazinone as well as phthalazinone analogues displayed moderate analgesic activity at 40 mg/kg. In general, all pyridazinone derivatives showed activity better than their phthalazinone counterparts.

PEG mediated synthesis and biological evaluation of asymmetrical pyrazole curcumin analogues as potential analgesic, anti-inflammatory and antioxidant agents.

The new series of asymmetrical pyrazole curcumin analogues 4a-g were synthesized by using polyethylene glycol (PEG-400) as a green reaction medium and evaluated for their in vivo analgesic and in vitro antioxidant (H2 O2 , DPPH, Ferrous reducing power and Nitric oxide scavenging activity) and anti-inflammatory activities. All the compounds synthesized 4a-g showed the potential to demonstrate analgesic activity as compared to the standard ibuprofen. Among the tested series, compounds 4e and 4b exhibited good hydrogen peroxide scavenging activity as compared to the standard butylated hydroxy toluene (BHT). Compounds 4b, 4d, 4f, and 4g showed good DPPH free radical scavenging activity. Compounds 4b, 4c, 4d, 4e and 4g showed excellent ferrous-reducing power activity, whereas all the compounds showed better nitric oxide scavenging activity than standard ascorbic acid. Additionally, all the synthesized compounds were also screened for their in vitro anti-inflammatory activity. Compounds 4b, 4d, 4f and 4g showed good anti-inflammatory activity as compared to standard diclofenac sodium.

Synthesis and biological evaluation of some novel 1-substituted fentanyl analogs in Swiss albino mice.

Fentanyl [N-(1-phenethyl-4-piperidinyl)propionanilide] is a potent opioid analgesic agent, but a has narrow therapeutic index. We reported earlier on the synthesis and bioefficacy of fentanyl and its 1-substituted analogs (1–4) in mice. Here we report the synthesis and biological evaluation of four additional analogs, viz. N-isopropyl-3-(4-(N-phenylpropionamido)piperidin-1-yl)propanamide (5), N-t-butyl-3-(4-(N-phenylpropionamido)piperidin-1-yl)propanamide (6), isopropyl 2-[4-(N-phenylpropionamido)piperidin-1-yl]propionate (7) and t-butyl 2-[4-(N-phenylpropionamido)piperidin-1-yl]propionate (8). The median lethal dose (LD50) determined by intravenous, intraperitoneal and oral routes suggests these analogs to be comparatively less toxic than fentanyl. On the basis of observational assessment on spontaneous activities of the central, peripheral, and autonomic nervous systems, all the analogs were found to be similar to fentanyl. Naloxone hydrochloride abolished the neurotoxic effects of these analogs, thereby ascertaining their opioid receptor-mediated effects. All the analogs displayed significant analgesic effects, measured by formalin-induced hind paw licking and tail immersion tests at their respective median effective dose (ED50). They also exhibited 8–12 fold increase in therapeutic index over fentanyl. However, 5 and 6 alone produced lower ED50 (20.5 and 21.0 µg/kg, respectively) and higher potency ratio (1.37 and 1.33, respectively) compared to fentanyl. They could thus be considered for further studies on pain management.

Pharmacological and structure-activity relationship evaluation of 4-aryl-1-diphenylacetyl(thio)semicarbazides.

This article describes the synthesis of six 4-aryl-(thio)semicarbazides (series a and b) linked with diphenylacetyl moiety along with their pharmacological evaluation on the central nervous system in mice and computational studies, including conformational analysis and electrostatic properties. All thiosemicarbazides (series b) were found to exhibit strong antinociceptive activity in the behavioural model. Among them, compound 1-diphenylacetyl-4-(4-methylphenyl)thiosemicarbazide 1b was found to be the most potent analgesic agent, whose activity is connected with the opioid system. For compounds from series a significant anti-serotonergic effect, especially for compound 1-diphenylacetyl-4-(4-methoxyphenyl)semicarbazide 2b was observed. The computational studies strongly support the obtained results.

The antinociceptive effect of intravenous imipramine in colorectal distension-induced visceral pain in rats: The role of serotonergic and noradrenergic receptors

It has been shown that imipramine, a tricyclic antidepressant (TCA), is a potent analgesic agent. However, the effect of imipramine on visceral pain has not been extensively investigated. In the current study, our aim was to characterise the putative analgesic effect of intravenous imipramine on visceral pain in rats. Our second aim was to assess the involvement of serotonergic (5-HT2, 3, 4) and noradrenergic (α2A, 2B, 2C) receptor subtypes in this putative antinociceptive effect of imipramine. Male Sprague Dawley rats (250–300g) were implanted with venous catheters for drug administration and implanted with enamelled nichrome electrodes for electromyography of the external oblique muscles. Noxious visceral stimulation was applied via by colorectal distension (CRD). The visceromotor responses (VMRs) to CRD were quantified electromyographically before and after imipramine administration at 5, 15, 30, 60, 90 and 120min. In the antagonist groups, the agents were administered 10min before imipramine. The administration of imipramine (5–40mg/kg) produced a dose-dependent reduction in VMR. The administration of yohimbine (a nonselective α2-adrenoceptor antagonist, 1mg/kg), BRL-44408 (an α2A-adrenoceptor antagonist, 1mg/kg) or MK-912 (an α2C-adrenoceptor antagonist, 300μg/kg) but not imiloxan (an α2B-adrenoceptor antagonist, 1mg/kg) inhibited the antinociceptive effect of imipramine (20mg/kg). Additionally, ketanserin (a 5-HT2 receptor antagonist, 0.5, 1, and 2mg/kg) and GR113808 (a 5-HT4 receptor antagonist, 1mg/kg) enhanced, and ondansetron (a 5-HT3 receptor antagonist, 0.5, 1, and 2mg/kg) failed to alter the imipramine-induced antinociceptive effect. Our data demonstrated that, in the CDR-induced rat visceral pain model, intravenous imipramine appeared to have antinociceptive potential and that α2A-/α2C-adrenoceptors and 5-HT2/5-HT4 receptors may be responsible for the antinociceptive effect of imipramine on visceral pain in rats.

Analgesic and Anti-Inflammatory Activities of some Transition Metal Schiff Base Complexes

Analgesic and anti-inflammatory activities of four transition metal complexes of a Schiff base derived from salicylaldehyde and glycine, viz. [N-salicylideneglycinato diaqua cobalt(II) dimer] (SGCo)2, [N-salicylideneglycinato-di-aqua-nickel(ll)dimer] (SGN)2, [N-salicylideneglycinato-aqua-copper(II)] (SGC) and [N-salicylideneglycinato diaqua zinc(II) dimer] (SGZ)2 were studied in swiss albino mice. 10 mg/kg (p.o) dose for each compound were selected throughout the research work. The analgesic activity was determined by acetic acid induced writhing and tail immersion methods. All such data were compared with standard drugs at the dose of 10 mg/kg (p.o. The anti-inflammatory activity of the test compounds was determined by the carragenan induced mice paw edema inhibition method.). Analgesic and anti-inflammatory activities of the test compounds at 10 mg/kg (p.o.) were quite comparable to those of standard drugs at 10 mg/kg (p.o.). All these compounds can be considered as potent analgesic and anti-inflammatory agents.

Analgesic and Anti-Inflammatory Activities of some Transition Metal Schiff Base Complexes

Analgesic and anti-inflammatory activities of four transition metal complexes of a Schiff base derived from salicylaldehyde and glycine, viz. [N-salicylideneglycinato diaqua cobalt(II) dimer] (SGCo)2, [N-salicylideneglycinato-di-aqua-nickel(ll)dimer] (SGN)2, [N-salicylideneglycinato-aqua-copper(II)] (SGC) and [N-salicylideneglycinato diaqua zinc(II) dimer] (SGZ)2 were studied in swiss albino mice. 10 mg/kg (p.o) dose for each compound were selected throughout the research work. The analgesic activity was determined by acetic acid induced writhing and tail immersion methods. All such data were compared with standard drugs at the dose of 10 mg/kg (p.o. The anti-inflammatory activity of the test compounds was determined by the carragenan induced mice paw edema inhibition method.). Analgesic and anti-inflammatory activities of the test compounds at 10 mg/kg (p.o.) were quite comparable to those of standard drugs at 10 mg/kg (p.o.). All these compounds can be considered as potent analgesic and anti-inflammatory agents.

Huwentoxin-XVI, an analgesic, highly reversible mammalian N-type calcium channel antagonist from Chinese tarantula Ornithoctonus huwena

N-type calcium channels play important roles in the control of neurotransmission release and transmission of pain signals to the central nervous system. Their selective inhibitors are believed to be potential drugs for treating chronic pain. In this study, a novel neurotoxin named Huwentoxin-XVI (HWTX-XVI) specific for N-type calcium channels was purified and characterized from the venom of Chinese tarantula Ornithoctonus huwena. HWTX-XVI is composed of 39 amino acid residues including six cysteines that constitute three disulfide bridges. HWTX-XVI could almost completely block the twitch response of rat vas deferens to low-frequency electrical stimulation. Electrophysiological assay indicated that HWTX-XVI specifically inhibited N-type calcium channels in rat dorsal root ganglion cells (IC50 ∼60 nM). The inhibitory effect of HWTX-XVI on N-type calcium channel currents was dose-dependent and similar to that of CTx-GVIA and CTx-MVIIA. However, the three peptides exhibited markedly different degrees of reversibility after block. The toxin had no effect on voltage-gated T-type calcium channels, potassium channels or sodium channels. Intraperitoneal injection of the toxin HWTX-XVI to rats elicited significant analgesic responses to formalin-induced inflammation pain. Toxin treatment also changed withdrawal latency in hot plate tests. Intriguingly, we found that intramuscular injection of the toxin reduced mechanical allodynia induced by incisional injury in Von Frey test. Thus, our findings suggest that the analgesic potency of HWTX-XVI and its greater reversibility could contribute to the design of a novel potential analgesic agent with high potency and low side effects.

Non-carboxylic Analogues of Aryl Propionic Acid: Synthesis, Anti-inflammatory, Analgesic, Antipyretic and Ulcerogenic Potential

As a part of ongoing studies in developing new potent anti-inflammatory and analgesic agents, a series of novel 6-methoxy naphthalene derivatives was efficiently synthesized and characterized by spectral and elemental analyses. The newly synthesized compounds were evaluated for their anti-inflammatory activities using carrageenin-induced rat paw edema model, analgesic activities using acetic acid induced writhing model in mice and anti-pyretic activity using yeast induced hyperpyrexia method as well as ulcerogenic effects. Among the synthesized compounds, thiourea derivative (6a, e) exhibited higher anti-inflammatory activity than the standard drug naproxen in reduction of the rat paw edema (88.71, 89.77%) respectively. All of the non-carboxylic tested compounds were found to have promising anti-inflammatory, analgesic and antipyretic activity, while were devoid of any ulcerogenic effects.

Antinociceptive properties of new coumarin derivatives bearing substituted 3,4-dihydro-2H-benzothiazines

BackgroundCoumarins are an important class of widely distributed heterocyclic natural products exhibiting a broad pharmacological profile. In this work, a new series of coumarins bearing substituted 3,4-dihydro-2H-benzothiazines were described as potential analgesic agents. The clinical use of NSAIDs as traditional analgesics is associated with side effects such as gastrointestinal lesions and nephrotoxicity. Therefore, the discovery of new safer drugs represents a challenging goal for such a research area.ResultsThe target compounds 3-(3-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-yl)-2H-chromen-2-ones 2a-u were synthesized and characterized by spectral data. The antinociceptive properties of target compounds were determined by formalin-induced test and acetic acid-induced writhing test in mice. Among the tested compounds, compound 2u bearing 2-(4-(methylsulfonyl)benzoyl)- moiety on benzothiazine ring and 4-(methylsulfonyl)phenacyloxy- group on the 7 position of coumarin nucleus showed better profile of antinocecieption in both models. It was more effective than mefenamic acid during the late phase of formalin-induced test as well as in the acetic acid-induced writhing test.ConclusionConsidering the significant antinoceciptive action of phenacyloxycoumarin derivatives, compound 2u prototype might be further used as model to obtain new more potent analgesic drugs.

Oxycodone/naloxone as a therapeutic option in a patient with chronic pain and opioid-induced bowel dysfunction.

Oxycodone/naloxone as a therapeutic option in a patient with chronic pain and opioid-induced bowel dysfunction.

Synthesis, analgesic, anti-inflammatory and in vitro antimicrobial activities of some novel isoxazole coupled quinazolin-4(3H)-one derivatives

A series of novel isoxazole coupled quinazolin-4(3H)-one derivatives were synthesized and characterized by FT-IR, 1H NMR, mass spectroscopy and bases of elemental analysis with the aim of developing potent analgesic, anti-inflammatory and antimicrobial agents. Tail-flick technique, carrageenan-induced foot paw edema test and agar streak dilution test were performed for screening analgesic, anti-inflammatory and in vitro antimicrobial activity respectively. Moreover all compounds were examined for its ulcerogenicity. Results revealed that entire series of compounds exhibited mild to good analgesic, anti-inflammatory and antimicrobial activity with low to moderate ulcer index. The relationship between the functional group variation and the biological activity of the evaluated compounds was discussed. Out of various synthesized compounds, 2-methyl-3-(4-(5-(4-(trifluoromethyl)phenyl) isoxazol-3-yl)phenyl)quinazolin-4(3H)-one 5e was found to be the most active compound.