Antinociceptive effect of PnTx4(5-5), a peptide from Phoneutria nigriventer spider venom, in rat models and the involvement of glutamatergic system

The venom of Phoneutria nigriventer spider is a source of numerous bioactive substances, including some toxins active in insects. An example is PnTx4(5-5) that shows a high insecticidal activity and no apparent toxicity to mice, although it inhibited NMDA-evoked currents in rat hippocampal neurons. In this work the analgesic activity of PnTx4(5-5) (renamed Γ-ctenitoxin-Pn1a) was investigated. Methods: The antinociceptive activity was evaluated using the paw pressure test in rats, after hyperalgesia induction with intraplantar injection of carrageenan or prostaglandin E2 (PGE2). Results: PnTx4(5-5), subcutaneously injected, was able to reduce the hyperalgesia induced by PGE2 in rat paw, demonstrating a systemic effect. PnTx4(5-5) administered in the plantar surface of the paw caused a peripheral and dose-dependent antinociceptive effect on hyperalgesia induced by carrageenan or PGE2. The hyperalgesic effect observed in these two pain models was completely reversed with 5 µg of PnTx4(5-5). Intraplantar administration of L-glutamate induced hyperalgesic effect that was significantly reverted by 5 μg of PnTx4(5-5) injection in rat paw. Conclusion: The antinociceptive effect for PnTx4(5-5) was demonstrated against different rat pain models, i.e. induced by PGE2, carrageenan or glutamate. We suggest that the antinociceptive effect of PnTx4(5-5) may be related to an inhibitory activity on the glutamatergic system.(AU)

A spider derived peptide, PnPP-19, induces central antinociception mediated by opioid and cannabinoid systems

Some peptides purified from the venom of the spider Phoneutria nigriventer have been identified as potential sources of drugs for pain treatment. In this study, we characterized the antinociceptive effect of the peptide PnPP-19 on the central nervous system and investigated the possible involvement of opioid and cannabinoid systems in its action mechanism. Methods Nociceptive threshold to thermal stimulation was measured according to the tail-flick test in Swiss mice. All drugs were administered by the intracerebroventricular route. Results PnPP-19 induced central antinociception in mice in the doses of 0.5 and 1 g. The non-selective opioid receptor antagonist naloxone (2.5 and 5 g), -opioid receptor antagonist clocinnamox (2 and 4 g), -opioid receptor antagonist naltrindole (6 and 12 g) and CB1 receptor antagonist AM251 (2 and 4 g) partially inhibited the antinociceptive effect of PnPP-19 (1 g). Additionally, the anandamide amidase inhibitor MAFP (0.2 g), the anandamide uptake inhibitor VDM11 (4 g) and the aminopeptidase inhibitor bestatin (20 g) significantly enhanced the antinociception induced by a low dose of PnPP-19 (0.5 g). In contrast, the -opioid receptor antagonist nor-binaltorphimine (10 g and 20 g) and the CB2 receptor antagonist AM630 (2 and 4 g) do not appear to be involved in this effect. Conclusions PnPP-19-induced central antinociception involves the activation of CB1 cannabinoid, - and -opioid receptors. Mobilization of endogenous opioids and cannabinoids might be required for the activation of those receptors, since inhibitors of endogenous substances potentiate the effect of PnPP-19. Our results contribute to elucidating the action of the peptide PnPP-19 in the antinociceptive pathway.

Antipyretic and analgesic activity of malvastrum coramandelianum linn

The effect of ethanol and acetone extracts of Malvastrum coramandelianum were investigated for antipyretic analgesic activity. The model used for antipyretic studies was pyrexia-induced rat model and for analgesic studies was tail tlick method in rats. These studies indicate that both extracts were showing significant antipyretic and analgesic properties. The preliminary phytochemical investigation indicates the presence of saponins and steroids

Synthesis of certain substituted pyrrolidines as analgesics

The synthesis of a series of N-[[2R]-1-ethyl or propyl-2-[4-methoxybenzyl]-pyrrolidin-3-yl]-N-phenyl acetamide or propionamide [la-d] was achieved, where R, R=methyl or ethyl with the aim to evaluate their analgesic activity. The adopted synthetic pathway of these compounds was illustrated Dieckmann cyclization of 2-[acyl-[2-ethoxycarboryl-ethyl]-amino]-3-[4-methoxy-phenyl]-propionic acid ethyl ester [7a, b] afforded [R]-ethyl 1-acetyl or propionyl-5-[4-methoxybenzyl]-4-oxopyrrolidine-3-carboxylate [6a and 6b], followed by deethoxycarboxylation. The target compounds 1a-d were synthesized Screening of the analgesic profile of the synthesized compounds showed that compounds 1b and 1c at dose level of 0.13mmol/kg. I p. exhibited the highest analgesic activity compared with morphine hydrochloride [0.004 mmol/kg. i.p]

Synthesis, biological evaluation and kinetic studies of glyceride prodrugs of diclofenac.

The prodrugs (glyceride derivatives) 3a and 3b of diclofenac were prepared by reacting 1, 2, 3-trihydroxy propane-1,3-dipalmitate/stearate with the acid chloride of diclofenac as potential prodrugs to reduce the gastrointestinal toxicity associated with them. These prodrugs were evaluated for their ulcerogenicity, anti-inflammatory and analgesic activity. It was found that the prodrugs were significantly less irritating to the gastric mucosa as indicated by severity index of 0.86, 0.78 compared to 1.6 of diclofenac. The prodrugs 3a and 3b showed better anti-inflammatory and analgesic activity than the parent drugs. The hydrolysis of prodrugs 3a and 3b were studied at pH 3, 4, 5 and 7.4. The HPLC analysis showed that the prodrugs were resistant to hydrolysis at pH 3, 4 and 5 indicating that they did not hydrolyze in acidic environment, whereas at pH 7.4 the prodrugs readily released the parent drug in significant quantities. The plasma levels of diclofenac were also analyzed by HPLC in rats after single oral dose of the prodrugs. The results indicated that the parent drugs were readily released. The concentration of diclofenac during the study was found higher in animals treated with prodrugs 3a and 3b compared with animals treated with diclofenac. The concentration of diclofenac was found to be 38.59, 33.6 and 30.36 microg/ml in animals treated with prodrugs 3a, 3b and diclofenac respectively. In conclusion, all these studies indicated that the glyceride prodrugs of diclofenac might be considered as potential biolabile prodrugs of diclofenac.

New azaindole derivatives as analgesic agent

The indole class of analgesics continues to be exposed to the pharmaceutical community. The synthesis and analgesic properties of these agents have been the subject of ongoing investigations. During the course of present research, efforts were made to evaluate the possible analgesic activity of various quaternary ammonium salts of 7 - azaindole to see whether one more nitrogen in the indole nucleus also responsible for analgesic activity

Synthesis and pharmacological evaluation of some new quinazoline- [1,2-C] quinazoline and 1,2,4-triazino [4,3-C] quinazoline analogs

Some new quinazolino [1,2-c] quinazolin-13-ones and 2,3,4,5-tetrahydro-2,5,-dioxo-1H-1,2,4 triazino [4,3-c] quinazolines were synthesized an characterized by both elemental and spectral analyses. Pharmacological evaluation of these erivatives showed that some viny1 derivatives of quinazolinoquinazolinone possess a significant hypnotic activity compared with phenobarbitone, whereas, other quinazolinoquinazolinones and trizinoquinazolins, showed mild non-narcotic analgesic activity compared with paracetamol

Synthesis and analgesic activity of N-arylakyl-N [2- [1-pyrrolidinyl] cyclohexyl] propanamides

The objective of this study was investigate further the presence of structural or functional analogies between the arylacetamide U50488 [1] and fentanyl [3]. The synthesis and in vitro analgesic activity [hot-plate test] of N-benzyl, N-[2-phenylethyl], and N-[3-phenylpropyl] derivatives of trans-[ +/- ] -N-[2-[1-pyrrolidinyl] cyclohexyl] propanamide [5-7, respectively] were discussed. Attempts to synthesize N-phenyl derivative 4 were also discussed. The lack of significant analgesic activity of 5-7 indicated the stringent structural requirement for the N-methyl-N-arylacetamide group of the k-selective opioid trans-[ +/- ]-2-[3, 4-dichlorophenyl]-N-methyl- N-[2- [1-pyrrolidinyl] cyclohexyl] acetamide [U50488][1]

Synthesis and analgesic activity of N-aryl/arylakyl 3- [1-pyrrolidinyl/piperidinyl] butyramides

Conjugate addition of pyrrolidine or piperidine to methyl crotonate and hydrolysis of the resulting methyl butyrates gave [ +/- ]-3-pyrrolidino or piperidino-butyric acids [17 and 18, respectively]. Coupling of these racemic acids to aralkylamines, L-phenylalaninamide, or L-phenylalanine methyl ester gave N-substituted butyramides 3-14 which were tested as analgesics using the hot-plate method. [ +/- ]-N-[2-phenethyl]-3-[1-pyrrolidinyl] butyramide [6] showed naloxone-attenuated analgesia but was considerably less potent than morphine and of shorter duration of action. Diastereomeric butyramides containing Phe residue [11-14] were less active analgesic than 6, but unlike N-aralkyl substituted derivatives, showed no toxic effects on locomotor activity at the high doses [30-60 mg/kg] used for testing. In all cases, analgesia was accompanied by inhibition of spontaneous motor activity and sedation

new type of piperidine derivative for analgesic activity

A new chemically synthesized piperidine derivative i.e. 1-methyl-1 [4-chloro] phenacyl-4-hydroxy piperidinium bromide was tested for analygesic activity in intact albino mice by tail flick latency in tail immersion method [Di Stasi et al., 1988]. The compound was administered orally in the doses of 50 mg/kg. Pethidine HCI 50 mg/kg was used as a reference drug. Control animals received only the vehicle. The result indicates that this compound exhibits highly significant analgesic activity

Synthesis and pharmacological activity of benzodipyran derivatives

1,2-dihydropyrano [3,2-g] [1] benzopyran-5-one derivatives IV a,b, VII and 1,2,3,4-tetrahydropyrano [3,2,g] [1] benzopypran-5-one derivatives VIII a-k were synthesized from the o-hydroxyaldehyde II. Compounds IVb, V, VIb, VII, VIIIb,c were tested for analgesic anti-inflammatory and ulcerogenic effects. Compounds VIIIb,c, VIb and VII were found to be potent analgesics with minimal ulcerogenic effect except VIb. None of the tested compounds was found to have anti-inflammatory activity

Spectrophotometric determination of paracetamol, Salicylamide and codeine phosphate in mixture

A spectrophotometric method for the analysis of a mixture of paracetamol, salicylamide and codeine phosphate is described. Paracetamol is determined by measuring its absorbance at lambdamax247 nm after separation from salicylamide and codeine phosphate at pH 8 by solvent extraction. The other two components were separated through the acid-dye method, where codeine phosphate forms an ion-pair complex with thymol blue at pH3 [lambdamax247 nm]. While salicylamide doesnot form such complex and can be estimated; without interference; at lambdamax307nm.beer-Lambert law was adhered to over the range of 2-14,4-24, and 5-30 micro g/ml for paracetamol, salicylamide and codeine phosphate respectively. This method was successfully applied for the analysis of laboratory synthetic mixture and also for pharmaceutical dosage from containing this ternary mixture

Quaternary ammonium salt derivatives of allylphenols with peripheral analgesic effect

Ammonium salt derivatives of natural allylphenols were synthesized with the purpose of obtaining potential peripheral analgesics. These drugs, by virtue of their physicochemical properties, would not be able to cross the blood brain barrier. Their inability to enter into the central nervous system (CNS) should prevent several adverse effects observed with classical opiate analgesics (Ferreira et al., 1984). Eugenol (1) O-methyleugenol (5) and safrole (9) were submitted to nitration, reduction and permethylation, leading to the ammonium salts 4, 8 and 12. Another strategy applied to eugenol (1), consisting in its conversion to a glycidic ether (13), opening the epoxide ring with secondary amines and methylation, led to the ammonium salts 16 and 17. All these ammonium salts showed significant peripheral analgesic action, in modified version of the Randall-Sellito test (Ferreira et al. 1978), at non-lethal doses. The ammonium salt 8 showed an activity comparable to that of methylnalorphinium, the prototype of an ideal peripheral analgesic (Ferreira et al., 1984).

Novel pyrazolone derivatives: synthesis and evaluation for analgesic activating

The synthesis of 3-amino-4-arylazo-2H-pyrazolin-5-one [III] was achieved by direct diazo-coupling of 3-aminopyrazolones or by hydrazinolysis of ethyl cyanoglyoxalate hydrazones. Acetylation of III gave the acetyl derivative IV or the pyrazol [3, 4-e] triazine V, depending on the reaction time. Benzoylation of III gave only the monobenzoyl derivative VI, whereas chloroaetylation gave the imidazol [1, 2-b] pyrazole VII. Representative examples of the products were tested for analgesic activity