Analgesic Compounds Research Articles

Occurrence and Ecotoxicological Risk Assessment of Analgesics in Wastewater

In this study, concentrations of analgesics including acetaminophen (ACETAM), indomethacin (INDO), acetylsalicylic acid (ACETYL ACID), phenylbutazone (PHENYL) and codeine (CO) were determined in wastewaters and risk assessment for organisms in the receiving environment was carried out. The analytical method for determination of analgesics in wastewater was optimized. The detection of analgesics was carried out by HPLC-MS/MS. Limit of detection (LOD) values for studied compounds were determined between 0.017 and 0.197 µg/L. Wastewater samples were taken from Konya Urban Wastewater Treatment Plant influent and effluent. ACETAM, CO, and INDO compounds were determined as 13000, 150, 80 ng/L in influent samples, respectively. ACETYL ACID and PHENYL were determined below limit of detection in influent samples. While INDO was determined about 84ng/L in effluent samples, ACETAM and CO were determined up to 25ng/L. The analgesic compounds indicated insignificant risk for algae, Daphnia magna and fish in the receiving environment

Mol-ecular and crystal structure of methyl 4-methyl-2,2-dioxo-1H-2λ6,1-benzo-thia-zine-3-carboxyl-ate.

The title compound, C11H11NO4S, possesses weak analgesic properties and is a source compound for the synthesis of highly active analgesic and anti-inflammatory compounds. The benzo-thia-zine ring adopts a conformation intermediate between twist-boat and sofa. The ester substituent is turned towards the endocyclic double bond because of steric repulsion. In the crystal, the mol-ecules form columns along the [001] direction, bound by N-H⋯O hydrogen bonds and stacking inter-actions.

In vivo analgesic effect of different extracts of Hopea odorata leaves in mice and in silico molecular docking and ADME/T property analysis of some isolated compounds from this plant.

Background The current study evaluates the analgesic effect of different extracts of Hopea odorata leaves in mice followed by molecular docking and absorption, distribution, metabolism, excretion, and toxicity (ADME/T) analysis of isolated compounds derived from the plant with the COX-1 enzyme. Methods In the present study, the dried leaves of H. odorata were subjected to extraction using methanol, ethanol, and water. In vivo analgesic activity was evaluated by using the acetic acid-induced writhing test and formalin-induced paw licking test, and in silico molecular docking and ADME/T study were performed using Schrödinger Maestro (version 11.1) and online-based tools, respectively, on eight isolated compounds. Results The results showed that the methanolic extract of leaves has highest significant dose-dependent analgesic activity at both 200 and 400 mg/kg followed by ethanolic extract of leaves. Among all the compounds, ampelopsin showed the best docking score of -7.055, ensuring strong binding affinity between the ligand and the receptor, and ADME/T analysis using Web-based tools ensures the compound has not violated Lipinski's rule of five indicating its safety consumption. Conclusions The result confirms the analgesic activity of H. odorata leaves in both in vivo and in silico assays. The data support ampelopsin to be a potent analgesic compound worthy of future clinical trials and its "drug-likeliness".

Structural Optimization and Characterization of Potent Analgesic Macrocyclic Analogues of Neurotensin (8–13)

The neurotensin receptors are attractive targets for the development of new analgesic compounds. They represent potential alternatives or adjuvants to opioids. Herein, we report the structural optimization of our recently reported macrocyclic peptide analogues of NT(8-13). The macrocycle was formed via ring-closing metathesis (RCM) between an ortho allylated tyrosine residue in position 11 and the side chain of alkene-functionalized amino acid in position 8 of NT(8-13). Minute modifications led to significant binding affinity improvement ( Ki improved from 5600 to 15 nM) with greatly improved plasma stability compared to NT(8-13). This study also delineates the structural features influencing these parameters. The signaling profiles of the new macrocycles were determined on the NTS1 receptor, and the physiological effects of the two most potent and stable analogues were assessed in vivo using rodent models. Both compounds displayed strong analgesic effects.

Effects of Juniperus phoenicea Hydroalcoholic Extract on Inflammatory Mediators and Oxidative Stress Markers in Carrageenan-Induced Paw Oedema in Mice.

Juniperus phoenicea (J. phoenicea) is a wild tree belonging to the Cupressaceae family, commonly used for the treatment of several disorders. This study aimed to evaluate the potential protective effects of J. phoenicea hydroethanolic extract (EtOH-H2OE) against oxidation, acute inflammation, and pain in mice models. For the purpose, chemical compounds of J. phoenicea EtOH-H2OE were also analyzed by GC-MS. The J. phoenicea EtOH-H2OE showed a potent antioxidant activity in vitro, thanks to its richness in phenolic and flavonoid compounds. Mice treated with EtOH-H2OE (100 mg/kg BW) showed reduced paw oedema formation and decreased malondialdehyde (MDA) content. The evaluation of antioxidant enzyme activities in paw oedema tissue after five hours of carrageenan induction showed a significant increase (P < 0.05). Inflammatory biomarkers explorations of J. phoenicea EtOH-H2OE-treated mice showed a restoration of the studied parameters to near-normal values. Furthermore, EtOH-H2OE of J. phoenicea produced a significant reduction of the number of abdominal writhes (P < 0.05) in a dose-dependent way. Phytochemical analysis of the J. phoenicea EtOH-H2OE by GC-MS showed the presence of hexadecanoic and stearic acids known as anti-inflammatory and analgesic compounds. Our investigation provided evidence that J. phoenicea EtOH-H2OE can effectively reduce the inflammation and pain in mice models.

Preclinical screening of a novel compound, 2-chlorothiophene for analgesic activity in swiss albino mice

Background: Pain is often the first indication of disease or injury. Analgesics are the drugs used clinically for controlling pain. They relieve pain as a symptom, without affecting its cause. Currently available options are nonsteroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics for the management of pain. Long term use of existing analgesics causes significant disturbances in the body system. A search for new, safe and cost effective analgesic compound is in progress. Hence a study on 2-chlorothiophene, a novel compound has been carried out in different experimental animal models.Methods: The central analgesic activity of 2-chlorothiophene was evaluated by eddy’s hot plate method and compared to standard central analgesic, morphine. Both central and peripheral analgesic activities of 2-chlorothiophene were evaluated by formalin induced paw licking in mice and compared to a standard drug, aspirin.Results: There were 40mg/kg dose of 2-chlorothiophene has shown maximum Pain Inhibition Percentage (PIP) of 46.15% at 60 min compared to 128% by morphine in eddy’s hot plate method. Under Formalin test, 20mg/kg dose of 2-chlorothiophene has shown maximum PIP of 22.91% in early phase and 52.63% in late phase compared to 12.5% and 47.37% by aspirin. The results were statistically significant with p&lt;0.05.Conclusions: 2-chlorothiophene found to have minimal central analgesic activity and significant peripheral analgesic activity as evident in eddy’s hot plate and formalin tests.

Raspberry-Pi based system for propofol monitoring

Induction of anesthesia with propofol is a largely adopted technique in hospital environments. The correct dosage of this compound is essential to avoid under- or over-anesthesia that may result in serious side-effects. Therefore, in clinical settings, long-term monitoring of propofol is of great importance. To this aim, in this work, we present the design and the validation of a custom-made, low-cost and portable Point-of-Care (PoC) system based on electrochemical detection for propofol monitoring. Fouling phenomenon due to phenolic oxidation of propofol has been overcome by adopting a Pencil Graphite Electrode (PGE) 3H as sensor. The validation of the system focused on testing the measurement speed through scan-rate analysis, which is important due to the fast clearance of propofol; and interference study with Paracetamol(APAP), since it is an analgesic compound frequently administered with propofol in medical practices.

Behavior of Micropollutants in Polishing Units that Combine Sorption and Biodegradation Mechanisms to Improve the Quality of Activated Sludge Effluent

The current study evaluated the removal of six micropollutants (estrone (E1); 17β-estradiol (E2); 17α-ethynylestradiol (EE2); ibuprofen (IBP), diclofenac (DCF), and paracetamol (PCT)) from the final effluent of an activated sludge domestic sewage treatment plant using polishing filters. Four polishing filters were assembled as columns and filled with a mixture of sand and vermiculite, sand and charcoal, sand and granulated activated carbon (9:1 by volume), and sand only. The column filters were placed near the outlet of a full-scale activated sludge treatment plant and were fed with a treated effluent containing from 4.71 to 28.93 ng L-1 of the target compounds at a hydraulic loading rate (HLR) of 50 m3 m−2 day−1. Samples were collected periodically from the influent (biologically treated sewage) and effluent of the four columns and analyzed for estrogens, anti-inflammatories, and analgesic compounds. Liquid samples were submitted to a solid phase extraction (SPE) and analyzed by gas chromatography coupled with mass spectrometry after their derivatization. Among the compounds found, diclofenac was distinguished by the high occurrence of detection in the samples (85%) and higher mean concentration (~ 17 ng L−1). High removal efficiency (> 90%) of the estrogens was observed in the polishing systems studied, while for the other targets, the removal efficiency varied from 10 to 30%. The concentration values of some compounds were low, probably due to rainfall during the sampling period.

Effects of human SULT1A3/SULT1A4 genetic polymorphisms on the sulfation of acetaminophen and opioid drugs by the cytosolic sulfotransferase SULT1A3

Sulfoconjugation has been shown to be critically involved in the metabolism of acetaminophen (APAP), morphine, tapentadol and O-desmethyl tramadol (O-DMT). The objective of this study was to investigate the effects of single nucleotide polymorphisms (SNPs) of human SULT1A3 and SULT1A4 genes on the sulfating activity of SULT1A3 allozymes toward these analgesic compounds. Twelve non-synonymous coding SNPs (cSNPs) of SULT1A3/SULT1A4 were investigated, and the corresponding cDNAs were generated by site-directed mutagenesis. SULT1A3 allozymes, bacterially expressed and purified, exhibited differential sulfating activity toward each of the four analgesic compounds tested as substrates. Kinetic analyses of SULT1A3 allozymes further revealed significant differences in binding affinity and catalytic activity toward the four analgesic compounds. Collectively, the results derived from the current study showed clearly the impact of cSNPs of the coding genes, SULT1A3 and SULT1A4, on the sulfating activity of the coded SULT1A3 allozymes toward the tested analgesic compounds. These findings may have implications in the pharmacokinetics as well as the toxicity profiles of these analgesics administered in individuals with distinct SULT1A3 and/or SULT1A4 genotypes.

Effect profile of paracetamol, Δ9-THC and promethazine using an evoked pain test battery in healthy subjects.

A battery of evoked pain tasks (PainCart) was developed to investigate the pharmacodynamic properties of novel analgesics in early-phase clinical research. As part of its clinical validation, compounds with different pharmacological mechanisms of actions are investigated. The aim was to investigate the analgesic effects of classic and nonclassic analgesics compared to a sedating negative control in a randomized placebo-controlled crossover study in 24 healthy volunteers using the PainCart. The PainCart consisted of pain tasks eliciting electrical, pressure, heat, cold and inflammatory pain. Subjective scales for cognitive functioning and psychotomimetic effects were included. Subjects were administered each of the following oral treatments: paracetamol (1000mg), Δ9-THC (10mg), promethazine (50mg) or matching placebo. Pharmacodynamic measurements were performed at baseline and repeated up to 10h postdose. Paracetamol did not show a significant reduction in pain sensation or subjective cognitive functioning compared to placebo. Promethazine induced a statistically significant reduction in PTT for cold pressor and pressure stimulation. Furthermore, reduced subjective alertness was observed. Δ9-THC showed a statistically significant decrease in PTT for electrical and pressure stimulation. Δ9-THC also demonstrated subjective effects, including changes in alertness and calmness, as well as feeling high and psychotomimetic effects. This study found a decreased pain tolerance due to Δ9-THC and promethazine, or lack thereof, using an evoked pain task battery. Pain thresholds following paracetamol administration remained unchanged, which may be due to insufficient statistical power. We showed that pain thresholds determined using this pain test battery are not driven by sedation. The multimodal battery of evoked pain tasks utilized in this study may play an important role in early-phase clinical drug development. This battery of pain tasks is not sensitive to the effects of sedation alone, and thus suitable to investigate the analgesic potential of novel analgesic compounds.

Optimization of Photooxidative Removal of Phenazopyridine from Water

The photooxidative removal of analgesic pharmaceutical compound phenazopyridine (PhP) from aqueous solutions by UV/H2O2 system with a re-circulated photoreactor was investigated. Response surface methodology (RSM) was employed to optimize the effect of operational parameters on the photooxidative removal efficiency. The investigated variables were: the initial PhP and H2O2 concentrations, irradiation time, volume of solution and pH. The analysis of variance (ANOVA) of quadratic model demonstrated that the described model was highly significant. The predicted values of the photooxidative removal efficiency were found to be in a fair agreement with experimental values (R2 = 0.9832, adjusted R2 = 0.9716). The model predicted that the optimal reaction conditions for a maximum removal of PhP (>98%) were: initial PhP concentration less than 23 mg L–1, initial concentration of H2O2 higher than 470 mg L–1, solution volume less than 500 mL, pH close to 2 and irradiation time longer than 6 min.

Synthesis and Structure-Activity Relationships of LP1 Derivatives: N-Methyl-N-phenylethylamino Analogues as Novel MOR Agonists.

The opioid pharmacological profile of cis-(−)-N-normetazocine derivatives is deeply affected by the nature of their N-substituents. Here, our efforts were focused on the synthesis and pharmacological evaluation of novel derivatives of the lead LP1, a multitarget opioid analgesic compound featuring an N-phenylpropanamido substituent. LP1 derivatives 5a–d and 6a–d were characterized by flexible groups at the N-substituent that allow them to reposition themselves relative to cis-(−)-N-normetazocine nucleus, thus producing different pharmacological profiles at the mu, delta and kappa opioid receptors (MOR, DOR and KOR) in in vitro and in vivo assays. Among the series, compound 5c, with the best in vitro and in vivo profile, resulted a MOR agonist which displays a KiMOR of 6.1 nM in a competitive binding assay, and an IC50 value of 11.5 nM and an Imax of 72% in measurement of cAMP accumulation in HEK293 cells stably expressing MOR, with a slight lower efficacy than LP1. Moreover, in a mouse model of acute thermal nociception, compound 5c, intraperitoneally administered, exhibits naloxone-reversed antinociceptive properties with an ED50 of 4.33 mg/kg. These results expand our understanding of the importance of N-substituent structural variations in the opioid receptor profile of cis-(−)-N-normetazocine derivatives and identify a new MOR agonist useful for the development of novel opioid analgesics for pain treatment.

A Review on Chemical Advanced Oxidation Processes for Pharmaceuticals with Paracetamol as a Model Compound. Reaction Conditions, Intermediates and Total Mechanism

Background: In recent years, there has been a growing interest in the environmental relevance of the presence of several pharmaceutical compounds and their metabolites in water. To avoid further accumulation of these compounds and their metabolites in the aquatic environment, several research groups are investigating chemical and photochemical methods that could be applied in their destruction and subsequent removal from natural and wastewater. Objective & Method: Different chemical advanced oxidation processes are being developed to destroy organic pollutants in water. Most of these methods are based on the production of HO• radicals that are known to be highly reactive and strong oxidizing agents. In aqueous chemical processes, these radicals can be generated using a variety of reagents and under different reaction conditions such as O3, H2O2/UV, TiO2/UV, O3/UV, H2O2/Fe2+, H2O2/Fe2+/UV and O3/Fe2+/Cu2+/UV. This review is a survey on recent advances in the application of different chemical advanced oxidation processes to mineralize pharmaceuticals. Paracetamol was selected as a model compound since its structure is the main component or metabolite of several anesthetic and analgesic compounds. The degradation of paracetamol by different advanced oxidation methods has been investigated by a combination of techniques (TOC, UV-Vis, IR, HPLC and GC-MS) in order to determine the optimal reaction conditions, kinetics, intermediate and product compounds generated. Conclusion: Understanding the basic concepts about reaction conditions, intermediates and mechanistic details on mineralization of paracetamol will be quite useful for future applications of several techniques in the removal of this and other structurally related pharmaceutical and aromatic compounds from water. Keywords: Paracetamol, ozonolysis, Fenton, photo-Fenton, TiO2-photocatalysis, pharmaceutical compounds, aromatic compounds.

Preclinical characterization of three transient receptor potential vanilloid receptor 1 antagonists for early use in human intradermal microdose analgesic studies.

The transient receptor potential vanilloid receptor 1 (TRPV1) is a nonselective cation channel involved in the mediation of peripheral pain to the central nervous system. As such, the TRPV1 is an accessible molecular target that lends itself well to the understanding of nociceptive signalling. This study encompasses preclinical investigations of three molecules with the prospect to establish them as suitable analgesic model compounds in human intradermal pain relief studies. The inhibitory effectiveness was evaluated by means of invitro assays, TRPV1 expressing Chinese hamster ovary cells (CHO-K1) and rat dorsal root ganglion cultures in fluorescent imaging plate reader and whole cell patch clamp systems, as well as invivo by capsaicin-evoked pain-related behavioural response studies in rat. Secondary pharmacology, pharmacokinetics and preclinical safety were also assessed. In vitro, all three compounds were effective at inhibiting capsaicin-activated TRPV1. The concentration producing 50% inhibition (IC50 ) determined was in the range of 3-32nmol/L and 10-501nmol/L using CHO-K1 and dorsal root ganglion cultures, respectively. In vivo, all compounds showed dose-dependent reduction in capsaicin-evoked pain-related behavioural responses in rat. None of the three compounds displayed any significant activity on any of the secondary targets tested. The compounds were also shown to be safe from a toxicological, drug metabolism and pharmacokinetic perspective, for usage in microgram doses in the human skin. The investigated model compounds displayed ideal compound characteristics as pharmacological and translational tools to address efficacy on the human native TRPV1 target in human skin insitu. This work details the pharmaceutical work-up of three TRPV1-active investigational compounds, to obtain regulatory approval, for subsequent use in humans. This fast and cost-effective preclinical development path may impact research beyond the pain management area, as it allows human target engagement information gathering early in drug development.

Analysis of a Quantitative Relationship Between the Structure and Analgesic Activity of Meperidin Derivatives Using Semi-Empirical AM1 Method

&lt;p&gt;This research aims were to analize a quantitative relationship between the structure and analgesic activity of meperidine derivatives and to determine the Hansch equation between meperidine derivatives and their analgesic activity. The study was done by computer calculation (in sillico) using semiempirical method of AM1. The first stage was molecules modelling of meperidine derivative compounds, followed with performing the process of geometric optimization. The second step was to determine the descriptor value in the form of electronic, steric, and hydrophobic descriptors. The last stage was done by statistics analysis using multiple regressions with backward model. The results showed that analgesic activity was significantly influenced by variation of descriptors, especially electronic descriptor which has more dominant influence than steric and hydrophobic descriptors. The most influential descriptor is the charge on N atoms, since N atoms are an important component in analgesic compounds.&lt;/p&gt;

Suitability of Stimuli evoked Hypersensitivities in Hind paws as a Clinically Relevant Pain Behavioural Measure in Rat Model of Walker 256 Breast Cancer Cellinduced Bone Pain: An Overview

Metastases of breast cancer cells to the axial skeleton causes excruciating pain. The nature of pain hypersensitivities in metastasized bones is very complex due to the interplay of inflammatory, neuropathic and cancer-specific pain components. The existing drugs typically used to treat breast cancer-induced bone pain are inefficacious and often exhibit severe side effects. Hence, it remains to be an important goal of the ongoing research activities to seek novel analgesic compounds with better efficacy and tolerability. One of the key aspects in the process of understanding the mechanisms of pain progression and drug discovery to mitigate the hypersensitivities is employment of suitable preclinical animal models that mimic the complex human pathophysiology of breast cancer induced bone pain. Walker 256 breast cancer cell- induced bone pain model in rats is one such model that is known to show key resemblances to the clinical pain associated with bony metastases. The commonly used methods to assess pain hypersensitivities in Walker 256 cell- induced bone pain model in rats include stimuli evoked techniques like von Frey assessment and Randall-Selitto test. While other methods like assessment of gait parameters or spontaneous pain can also be used as beneficial complementary tools, this short review majorly sheds light on suitability of the stimuli evoked pain assessment methods in the hind paws of rats as being clinically relevant measures of assessing breast cancer induced bone pain in Walker 256 cell induced bony metastases.

Novel anti-inflammatory and analgesic agents: synthesis, molecular docking and in vivo studies

Twelve new derivatives of benzothiazole bearing benzenesulphonamide and carboxamide were synthesised and investigated for their in vivo anti-inflammatory, analgesic and ulcerogenic activities. Molecular docking showed an excellent binding interaction of the synthesised compounds with the receptors, with 17c showing the highest binding energy (–12.50 kcal/mol). Compounds 17c and 17i inhibited carrageenan-induced rat paw oedema at 72, 76, and 80% and 64, 73, and 78% at 1 h, 2 h, and 3 h, respectively. In the analgesic activity experiment, compounds 17c, 17 g, and 17i had ED50 (µM/kg) of 96, 127, and 84 after 0.5 h; 102, 134, and 72 after 1 h and 89, 156, and 69 µM/kg after 2 h, respectively, which were comparable with 156, 72, and 70 µM/kg for celecoxib. The ulcerogenic index of the most active derivatives 17c and 17i were 0.82 and 0.89, respectively, comparable to 0.92 for celecoxib. The physicochemical studies of the new derivatives showed that they will not have oral bioavailability problems.

Determination of 63 compounds illegally added in tea, substitute tea and beverage foods by ultra-high performance liquid chromatography-tandem mass spectrometry

A method based on ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed for the simultaneous determination of 63 compounds illegally added in tea, substitute tea, and beverage products. The samples were extracted by ultrasonic extraction using methanol, and the analytes were separated on the Thermo Acclaim RSLC C18 chromatographic column (100 mm×2.1 mm, 2.2 μm) by gradient elution using 5 mmol/L ammonium formate solution containing 0.1% (v/v) formic acid and 0.1% (v/v) formic acid acetonitrile as the mobile phase. The electrospray ion source was operated in the positive ion mode using the dynamic multi-reaction monitoring (dMRM) method, and the results were quantified by the external standard method. The correlation coefficients (R2) of the linear calibration curves were greater than 0.99 in the corresponding mass concentration ranges, and the limits of quantification (LOQs) for the analytes were 0.10-2.50 mg/kg. The average recoveries at three spiked levels ranged from 62.4% to 129.4%. The RSDs of the injection precision and the repeatability of samples were in the range 0.3%-9.6% (n=6). Thus, the proposed method is simple, rapid, accurate, reliable, and applicable for the detection of the illegal addition of antipyretic and analgesic affect compounds in tea, substitute tea and beverage food.

ANTI-INFLAMMATORY AND ANALGESIC ACTIVITIES OF AVOCADO SEED (Persea americana Mill.)

The purpose of this research is to evaluate the anti-inflammatory and analgesic activities of infusion and methanolic extract from avocado seeds. The anti-inflammatory activity was determined using carrageenan-induced paw edema in mice. The analgesic activity was assessed using acetic acid stimuli to induce peripheral pain in mice. Results of this research showed that both all level doses of infusion and methanolic extract of avocado seeds have a significant reduction on the mice paw edema. All level doses of methanolic extract of avocado seeds have a significant reduction on the number of abdominal writhes induced by acetic acid, but only the lowest dose of infusion showed a significant reduction. Our findings suggest that avocado seeds contains potential anti-inflammatory and analgesic compounds which support its traditional use. Further phytochemical studies are required to determine the active compounds are actually responsible for such properties.

Schiff Bases Derived from 1-Aminoanthraquinone: A New Class of Analgesic Compounds

A series of Schiff bases 1-17 were synthesised by way of a facile condensation between 1-amino-anthraquinone with a variety of carbonyl compounds in the presence of a catalytic amount of dodeca-tungstosilicic acid/P2O5 under solvent free conditions at room temperature. These were charachterised by1H- and 13C-NMR, LCMS, FTIR and elemental analyses. All the compounds were screened for theiranalgesic activity using hot plate thermal stimuli method at dose of 10 and 30 mg/kg. Diclofenac sodiumwas used as a reference drug. All the compounds at dose of 10 and 30 mg/kg body weight showed thesignificant (p&lt;0.05) increase in latency time as compared to control (normal saline). Compound 5 showedexcellent activity after 120 min of drug administration (10 mg/kg) of body weight. Compound 10 wasfound to be potent (10.48±1.19s, 11.27±1.2s and 10.24±1.9s) at dose of 30 mg/kg at 30, 60 and 120 min,respectively when compared to the standard drug. Compound 6 (10.13±0.4s) was also found to be anexcellent analgesic compound at a dose of 30 mg/kg at 120 min. However, the studies on analgesic activityrevealed that some of the target compounds may be strong candidates as an analgesic drug.