morphine and Pain

Opioid analgesics have been used for thousands of years in the treatment of pain and related disorders, and have become among the most widely prescribed medications. Among opioid analgesics, mu opioid receptor (MOR) agonists are the most commonly used and are indicated for acute and chronic pain management. However, their use results in a plethora of well-described side-effects. From selective delta opioid receptor (DOR) and kappa opioid receptor (KOR) agonists to multitarget MOR/DOR and MOR/KOR ligands, medicinal chemistry provided different approaches aimed at the development of opioid analgesics with an improved pharmacological and tolerability fingerprint. The emergent medicinal chemistry strategy to develop ameliorated opioid analgesics is based upon the concept that functional selectivity for G-protein signalling is necessary for the therapeutic effect, whether β-arrestin recruitment is mainly responsible for the manifestation of side effects, including the development of tolerance after repeated administrations. This review summarises most relevant biased MOR, DOR, KOR and multitarget MOR/DOR ligands synthesised in the last decade and their pharmacological profile in "in vitro" and "in vivo" studies. Such biased ligands could have a significant impact on modern drug discovery and represent a new strategy for the development of better-tolerated drug candidates.

Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Humans; Molecular Structure; Pain; Pain Management; Receptors, Opioid, mu; Structure-Activity Relationship

Still nowadays pain is one of the most common disabling conditions and yet it remains too often unsolved. Analgesic opioid drugs, and mainly MOR agonists such as morphine, are broadly employed for pain management. MOR activation, however, has been seen to cause not only analgesia but also undesired side effects. A potential pain treatment option is represented by the simultaneous targeting of different opioid receptors. In fact, ligands possessing multitarget capabilities led to an improved pharmacological fingerprint. This review focuses on the examination of multitarget opioid ligands which have been distinguished in peptide and non-peptide and further listed as bivalent and bifunctional ligands. Moreover, the potential of these compounds, both as analgesic drugs and pharmacological tools to explore heteromer receptors, has been stressed.

Topics: Analgesics, Opioid; Animals; Humans; Ligands; Molecular Structure; Pain; Receptors, Opioid

Paracetamol and NSAIDs, in particular acetylsalicylic acid (aspirin) and ibuprofen, are among the most used and environmentally released pharmaceutical drugs. The differences in international trends in the sale and consumption of mild analgesics reflect differences in marketing, governmental policies, habits, accessibility, disease patterns and the age distribution of each population. Biomonitoring indicates ubiquitous and high human exposure to paracetamol and to salicylic acid, which is the main metabolite of acetylsalicylic acid. Furthermore, evidence suggests that analgesics can have endocrine disruptive properties capable of altering animal and human reproductive function from fetal life to adulthood in both sexes. Medical and public awareness about these health concerns should be increased, particularly among pregnant women.

Topics: Acetaminophen; Analgesics, Non-Narcotic; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Commerce; Congenital Abnormalities; Drug Monitoring; Endocrine Disruptors; Environmental Exposure; Female; Humans; Ibuprofen; Meconium; Milk, Human; Molar; Pain; Pain Management; Pregnancy; Pregnancy Outcome; Prenatal Exposure Delayed Effects; Salicylic Acid; Tooth, Deciduous; Urogenital Abnormalities

Topics: Abdomen; Adolescent; Adult; Child; Child, Preschool; Cystic Fibrosis; Fatty Liver; Feces; Humans; Infant; Intestinal Absorption; Intestinal Diseases; Intestinal Mucosa; Intestinal Obstruction; Intestines; Lactose Intolerance; Meconium; Metabolism, Inborn Errors; Pain; Pancreas; Prognosis; Rectal Prolapse

The aim of this study was to investigate the effect of sacral massage on the presence of meconium-stained amniotic fluid and the duration of fetal descent during labor in pregnant women.. A total of 220 nulliparous women with singleton low-risk pregnancies in the vertex position at term were recruited. Eligible women were randomly assigned to either massage group or a control group. The massages were performed with friction and tapotement protocol. The massage was applied for 10 min each time by a midwife who is also an expert in the field, at the onset of contractions during the intrapartum period, when cervical dilatation reached 10 cm. The Wong-Baker faces pain rating scale was evaluated.. No significant difference was found between the length of the first stage of labor and the total length of delivery (p = 0.097 and 0.434), respectively. There was a significant difference between the two groups in terms of perineal injuries. Perineal injury was lower in the massaged group (p = 0.005). There was a low percentage of meconium-stained amniotic fluid in the massaged group. The difference between the groups was statistically significant. The duration of fetal descent was shorter in the massaged group (p < 0.001). A significant difference was found in Wong-Baker FACES pain rating scale scores. Lower scores were detected in the massaged group (p < 0.001).. Sacral massage has beneficial effects on mothers and babies in obstetric practice. In addition, applying massage during labor plays a significant role in reducing the presence of meconium-stained amniotic fluid and the duration of fetal descent.

Topics: Amniotic Fluid; Female; Humans; Infant, Newborn; Labor, Obstetric; Massage; Meconium; Pain; Pregnancy; Pregnancy Complications

Strong opioid analgesics, including morphine, are the mainstays for treating moderate to severe acute pain and alleviating chronic cancer pain. However, opioid-related adverse effects, including nausea or vomiting, sedation, respiratory depression, constipation, pruritus (itch), analgesic tolerance, and addiction and abuse liability, are problematic. In addition, the use of opioids to relieve chronic noncancer pain is controversial due to the "opioid crisis" characterized by opioid misuse or abuse and escalating unintentional death rates due to respiratory depression. Hence, considerable research internationally has been aimed at the "Holy Grail" of the opioid analgesic field, namely the discovery of novel and safer opioid analgesics with improved opioid-related adverse effects. In this Perspective, medicinal chemistry strategies are addressed, where structurally diverse nonmorphinan-based opioid ligands derived from natural sources were deployed as lead molecules. The current state of play, clinical or experimental status, and novel opioid ligand discovery approaches are elaborated in the context of retaining analgesia with improved safety and reduced adverse effects, especially addiction liability.

Topics: Analgesics, Opioid; Animals; Biological Products; Cell Line, Tumor; Chemistry, Pharmaceutical; Drug Discovery; Humans; Ligands; Pain; Peptides; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu

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Topics: Humans; NAV1.7 Voltage-Gated Sodium Channel; Pain; Quinolones; Structure-Activity Relationship; Sulfanilamide; Sulfonamides; Urea; Voltage-Gated Sodium Channel Blockers

The search for selective kappa opioid receptor (κOR) agonists with an improved safety profile is an area of interest in opioid research. In this work, a series of

Topics: Analgesics, Opioid; Animals; CHO Cells; Cricetulus; Hot Temperature; Humans; Male; Mice; Molecular Docking Simulation; Pain; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Thebaine

Endomorphins (EMs) are potent pharmaceuticals for the treatment of pain. Herein, we investigated several novel EM analogues with multiple modifications and oligoarginine conjugation. Our results showed that analogues 1-6 behaved as potent μ-opioid agonists and enhanced stability and lipophilicity. Analogues 5 and 6 administered centrally and peripherally induced significant and prolonged antinociceptive effects in acute pain. Both analogues also produced long-acting antiallodynic effects against neuropathic and inflammatory pain. Furthermore, they showed a reduced acute antinociceptive tolerance. Analogue 6 decreased the extent of chronic antinociceptive tolerance, and analogue 5 exhibited no tolerance at the supraspinal level. Particularly, they displayed nontolerance-forming antinociception at the peripheral level. In addition, analogues 5 and 6 exhibited reduced or no opioid-like side effects on gastrointestinal transit, conditioned place preference (CPP), and motor impairment. The present investigation established that multiple modifications and oligoarginine-vector conjugation of EMs would be helpful in developing novel analgesics with fewer side effects.

Topics: Analgesics; Analgesics, Opioid; Animals; Brain; Conditioning, Operant; Endorphins; Gastrointestinal Transit; Mice; Motor Activity; Pain; Peptides

Endomorphin (EM)-1 and EM-2 are the most effective endogenous analgesics with efficient separation of analgesia from the risk of adverse effects. Poor metabolic stability and ineffective analgesia after peripheral administration were detrimental for the use of EMs as novel clinical analgesics. Therefore, here, we aimed to establish new EM analogs via introducing different bifunctional d-amino acids at position 2 of [(2-furyl)Map

Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Drug Design; Formaldehyde; Male; Mice; Mice, Inbred Strains; Molecular Structure; Oligopeptides; Pain; Pain Measurement; Receptors, Opioid, mu; Structure-Activity Relationship

Herein, the synthesis and pharmacological characterization of an extended library of differently substituted N-methyl-14- O-methylmorphinans with natural and unnatural amino acids and three dipeptides at position 6 that emerged as potent μ/δ opioid receptor (MOR/DOR) agonists with peripheral antinociceptive efficacy is reported. The current study adds significant value to our initial structure-activity relationships on a series of zwitterionic analogues of 1 (14- O-methyloxymorphone) by targeting additional amino acid residues. The new derivatives showed high binding and potent agonism at MOR and DOR in vitro. In vivo, the new 6-amino acid- and 6-dipeptide-substituted derivatives of 1 were highly effective in inducing antinociception in the writhing test in mice after subcutaneous administration, which was antagonized by naloxone methiodide demonstrating activation of peripheral opioid receptors. Such peripheral opioid analgesics may represent alternatives to presently available drugs for a safer pain therapy.

Topics: Analgesics, Opioid; Animals; Cell Membrane; Dipeptides; Humans; Male; Mice; Morphine; Oxymorphone; Pain; Protein Binding; Receptors, Opioid, delta; Receptors, Opioid, mu; Structure-Activity Relationship

In order to discover a novel type of analgesic, we investigated dual activity ligands with TRPV1 antagonism and mu-opioid receptor affinity with the goal of eliciting synergistic analgesia while avoiding the side effects associated with single targeting. Based on a combination approach, a series of 4-benzyl-4-(dimethylamino)piperidinyl analogues were designed, synthesized and evaluated for their receptor activities. Among them, compound 49 exhibited the most promising dual-acting activity toward TRPV1 and the mu-opioid receptor in vitro. In vivo,49 displayed potent, dose-dependent antinociceptive activity in both the 1st and 2nd phases in the formalin assay. Consistent with its postulated mechanism, we confirmed that in vivo, as in vitro, compound 49 both antagonized TRPV1 and functioned as a mu-opioid agonist. This result indicates that dual-acting TRPV1 antagonist/mu-opioid ligands can be made and represent a new and promising class of analgesic.

Topics: Analgesics, Opioid; Animals; Cells, Cultured; CHO Cells; Cricetulus; Dose-Response Relationship, Drug; Drug Discovery; Humans; Ligands; Male; Mice; Mice, Inbred ICR; Molecular Structure; Pain; Receptors, Opioid; Structure-Activity Relationship; TRPV Cation Channels

The opioid and neuropeptide FF pharmacophore-containing chimeric peptide 0 (BN-9) was recently developed and produced potent nontolerance forming analgesia. In this study, 11 analogues of 0 were designed and synthesized. An in vitro cAMP assay demonstrated that these analogues behaved as multifunctional agonists at both opioid and NPFF receptors. In mouse tail-flick test, most of the analogues produced potent nontolerance forming antinociception. Notably, 11 (DN-9) was 33-fold more potent than 0 at analgesic effects, which was mediated by μ- and κ-opioid receptors. In addition, 11 also produced powerful analgesic effects in the formalin pain and CFA-induced chronic inflammatory pain models. Strikingly, following its repeated administration for 6 days, 11 did not produce antinociceptive tolerance in the tail-flick test and CFA-induced pain model. The present work indicates that it is reasonable to design multifunctional peptide ligands for opioid and NPFF receptors in a single molecule producing effective nontolerance forming antinociception.

Topics: Analgesics; Animals; Dose-Response Relationship, Drug; HEK293 Cells; Humans; Male; Mice; Mice, Inbred Strains; Molecular Structure; Pain; Peptides; Receptors, Neuropeptide; Receptors, Opioid, kappa; Receptors, Opioid, mu; Structure-Activity Relationship

In this study, we describe the design and synthesis of new N

Topics: Acetic Acid; Adenosine A2 Receptor Agonists; Analgesics; Animals; CHO Cells; Cricetulus; Cyclic AMP; Diamines; Dose-Response Relationship, Drug; Drug Design; Female; Humans; Mice; Molecular Structure; Pain; Pyrimidines; Receptor, Adenosine A2A; Structure-Activity Relationship; Thiazoles

Topics: Analgesics, Opioid; Animals; Cells, Cultured; CHO Cells; Cricetulus; Diterpenes; Diterpenes, Clerodane; Dose-Response Relationship, Drug; Male; Molecular Structure; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Salvia; Structure-Activity Relationship

Nine new grayanoids (1-9), together with 11 known compounds, were isolated from the roots of Rhododendron molle. The structures of the new compounds (1-9) were determined on the basis of spectroscopic analysis, including HRESIMS, and 1D and 2D NMR data. Compounds 4, 6, 12, and 14-20 showed significant antinociceptive activities in an acetic acid-induced writhing test. In particular, 14 and 15 were found to be more potent than morphine for both acute and inflammatory pain models and 100-fold more potent than gabapentin in a diabetic neuropathic pain model.

Topics: Amines; Analgesics; Animals; Cyclohexanecarboxylic Acids; Disease Models, Animal; Diterpenes; Drugs, Chinese Herbal; Female; Gabapentin; gamma-Aminobutyric Acid; Male; Mice; Molecular Structure; Morphine; Nuclear Magnetic Resonance, Biomolecular; Pain; Plant Roots; Rhododendron

The nociceptin opioid receptor (NOP) and its endogenous peptide ligand nociceptin/orphanin FQ have been shown to modulate the pharmacological effects of the classical opioid receptor system. Suppression of opioid-induced reward associated with mu-opioid receptor (MOP)-mediated analgesia, without decreasing anti-nociceptive efficacy, can potentially be achieved with NOP agonists having bifunctional agonist activity at MOP, to afford 'non-addicting' analgesics. In Part II of this series, we describe a continuing structure-activity relationship (SAR) study of the NOP-selective piperidin-4-yl-1,3-dihydroindol-2-one scaffold, to obtain bifunctional activity at MOP, and a suitable ratio of NOP/MOP agonist activity that produces a non-addicting analgesic profile. The SAR reported here is focused on the influence of various piperidine nitrogen aromatic substituents on the ratio of binding affinity and intrinsic activity at both the NOP and MOP receptors.

Topics: Analgesics; Animals; Ligands; Mice; Models, Animal; Nociceptin Receptor; Pain; Piperidines; Protein Binding; Receptors, Opioid; Receptors, Opioid, mu; Structure-Activity Relationship

The μ-opioid receptor (MOR) is the major opioid receptor targeted by most analgesics in clinical use. However, the use of all known MOR agonists is associated with severe adverse effects. We reported that the 1-phenyl-3,6,6-trimethyl-1,5,6,7-tetrahydro-4H-indazol-4-ones are novel opioid receptor agonists. Subsequent structural modification resulted in the potent MOR/KOR (κ-opioid receptor) agonists 19, 20, and 21. Testing the analgesic effect of these in WT B6 mice (tail-flick test) gave ED50 values of 8.4, 10.9, and 26.6mg/kg, respectively. The 1-phenyl-3,6,6-trimethyl-1,5,6,7-tetrahydro-4H-indazol-4-one core could be addressed in 1 or 2 synthetic steps with moderate to high percent of yield. In the adenylyl cyclase assay, compound 19 displayed a MOR/KOR agonist profile, with IC50 values of 0.73 and 0.41μM, respectively. Current results suggest that compound 19 is a promising lead to go further development and in vitro/in vivo adverse effects studies.

Topics: Analgesics; Animals; Dose-Response Relationship, Drug; Drug Discovery; HEK293 Cells; Humans; Indazoles; Mice; Mice, Congenic; Molecular Structure; Pain; Pain Measurement; Receptors, Opioid, kappa; Receptors, Opioid, mu; Structure-Activity Relationship; Tail

Pain is the most common reason a patient sees a physician. Nevertheless, the use of typical painkillers is not completely effective in controlling all pain syndromes; therefore further attempts have been made to develop improved analgesic drugs. The present study was undertaken to evaluate the antinociceptive properties of physalins B (1), D (2), F (3), and G (4) isolated from Physalis angulata in inflammatory and centrally mediated pain tests in mice. Systemic pretreatment with 1-4 produced dose-related antinociceptive effects on the writhing and formalin tests, traditional screening tools for the assessment of analgesic drugs. On the other hand, only 3 inhibited inflammatory parameters such as hyperalgesia, edema, and local production of TNF-α following induction with complete Freund's adjuvant. Treatment with 1, 3, and 4 produced an antinociceptive effect on the tail flick test, suggesting a centrally mediated antinociception. Reinforcing this idea, 2-4 enhanced the mice latency reaction time during the hot plate test. Mice treated with physalins did not demonstrate motor performance alterations. These results suggest that 1-4 present antinociceptive properties associated with central, but not anti-inflammatory, events and indicate a new pharmacological property of physalins.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Disease Models, Animal; Edema; Freund's Adjuvant; Hyperalgesia; Male; Mice; Molecular Structure; Pain; Pain Measurement; Physalis; Secosteroids; Tumor Necrosis Factor-alpha

Hecogenin is a sapogenin present in the leaves of species from the Agave genus, with a wide spectrum of reported pharmacological activities. The present study was undertaken to evaluate whether hecogenin acetate (1) has antinociceptive properties and to determine its mechanism of action. The nociceptive threshold was evaluated using the tail flick test in mice. Mice motor performance was evaluated in a Rotarod test. By using Fos expression as a marker of neural activation, the involvement of the periaqueductal gray in 1-induced antinociception was evaluated. Intraperitoneal administration of 1 (5-40 mg/kg) produced a dose-dependent increase in the tail flick latency time compared to vehicle-treated group (p < 0.01). Mice treated with 1 (40 mg/kg) did not show motor performance alterations. The antinociception of 1 (40 mg/kg) was prevented by naloxone (nonselective opioid receptor antagonist; 5 mg/kg), CTOP (μ-opioid receptor antagonist; 1 mg/kg), nor-BNI (κ-opioid receptor antagonist; 0.5 mg/kg), naltrindole (δ-opioid receptor antagonist; 3 mg/kg), or glibenclamide (ATP-sensitive K(+) channel blocker; 2 mg/kg). Systemic administration of 1 (5-40 mg/kg) increased the number of Fos positive cells in the periaqueductal gray. The present study has demonstrated for the first time that 1 produces consistent antinociception mediated by opioid receptors and endogenous analgesic mechanisms.

Topics: Agave; Analgesics; Animals; Glyburide; KATP Channels; Male; Mice; Molecular Structure; Naltrexone; Pain; Periaqueductal Gray; Plant Leaves; Receptors, Opioid, kappa; Receptors, Opioid, mu; Spiro Compounds; Steroids

A series of carbamic acid 1-phenyl-3-(4-phenyl-piperazine-1-yl)-propyl ester derivatives were synthesized through discovery strategies for balancing target-based in vitro screening and phenotypic in vivo screening. All the newly synthesized compounds were screened for their analgesic activities and compared with standard drug morphine. Among them, compound 44r, a potent analgesic agent that has favorable pharmacokinetic properties in rats and most importantly, has a wide safety margin. We demonstrated with in vitro and in vivo functional assays that its analgesic activity might be through 5-HT(2A) antagonism to some extent. Hence, it is concluded that there is ample scope for further study in developing compound 44r as a good lead candidate for an analgesic agent.

Topics: Analgesics; Animals; Carbamates; Esters; Mice; Molecular Structure; Morphine; Pain; Pain Measurement; Piperazines; Rats; Receptors, Serotonin, 5-HT2; Serotonin Antagonists; Structure-Activity Relationship

A series of derivatives of dihydrofuran-2(3H)-one (γ-butyrolactone, GBL) was synthesized and tested for anticonvulsant, neurotoxic and analgesic activity. In the anticonvulsant screening 10 lactones were effective in the maximal electroshock test (MES) at the highest doses (300 and 100 mg/kg, 0.5 h, ip, mice). Statistical analysis showed correlation between the anticonvulsant activity and relative lipophilicity parameters determined by experimental and computational methods (R(M0), ClogP and MlogP). Preliminary antinociceptive evaluation of selected derivatives revealed strong analgesic activity. The majority of the tested compounds showed high efficacy in animal models of acute pain (hot plate and writhing tests) and strong local anesthetic activity (modified tail immersion test). The obtained ED(50) values were comparable with such analgesics as acetylsalicylic acid and morphine.

Topics: 4-Butyrolactone; Analgesics; Anesthetics, Local; Animals; Anticonvulsants; Dose-Response Relationship, Drug; Electroshock; Male; Mice; Pain; Pain Measurement

The synthesis and the effect of a combination of 6-glycine and 14-phenylpropoxy substitutions in N-methyl- and N-cycloproplymethylmorphinans on biological activities are described. Binding studies revealed that all new 14-phenylpropoxymorphinans (11-18) displayed high affinity to opioid receptors. Replacement of the 14-methoxy group with a phenylpropoxy group led to an enhancement in affinity to all three opioid receptor types, with most pronounced increases in δ and κ activities, hence resulting in a loss of μ receptor selectivity. All compounds (11-18) showed potent and long-lasting antinociceptive effects in the tail-flick test in rats after subcutaneous administration. For the N-methyl derivatives 13 and 14, analgesic potencies were in the range of their 14-methoxy analogues 9 and 10, respectively. Even derivatives 15-18 with an N-cyclopropylmethyl substituent acted as potent antinociceptive agents, being several fold more potent than morphine. Subcutaneous administration of compounds 13 and 14 produced significant and prolonged antinociceptive effects mediated through peripheral opioid mechanisms in carrageenan-induced inflammatory hyperalgesia in rats.

Topics: Analgesics; Animals; Binding, Competitive; Guanosine 5'-O-(3-Thiotriphosphate); Magnetic Resonance Spectroscopy; Morphinans; N-substituted Glycines; Pain; Rats; Receptors, Opioid; Spectrometry, Mass, Electrospray Ionization; Spectroscopy, Fourier Transform Infrared; Structure-Activity Relationship

A series of N2-{2-[4-aryl(benzyl)-1-piperazinyl(piperidinyl)]ethyl}pyrrolo[3,4-d]pyridazinones 4 and related derivatives 5 were synthesized as potential analgesic agents. The structures of the new compounds were elucidated by micro, spectral and X-ray analysis. Analgesic activity of the compounds was investigated in the phenylbenzoquinone induced 'writhing' and 'hot plate' test in mice and at radioligand binding assay. At 'writhing' test all compounds, without exception, were more active than acetylsalicylic acid (ASA) with ED(50) values ranging from 0.04 to 11 mg/kg (i.p.) (ED(50) for ASA--39.15 mg/kg). Analgesic effect at the 'hot plate' test was observed for three compounds 4c,e,f at the dose 3-5 times higher then that of morphine (ED(50)-3.39 mg/kg). At radioligand binding assay of 4c,e,f only compound 4f exhibited affinity for the μ-opioid receptors similar to that of Tramadol. The acute toxicity of the pyrrolopyridazinones 4, 5 were also studied and non toxic effect was observed at the 2000 mg/kg (5a 1420 mg/kg) i.p. dose level. On the basis of the available pharmacological data S-A relationship is discussed. The preferred conformational characteristic of 4, taken 4c as an example, was also described.

Topics: Analgesics; Animals; Crystallography, X-Ray; Male; Mice; Models, Molecular; Pain; Pain Measurement; Pyridazines; Pyrroles; Structure-Activity Relationship

To discover analgesics for treating chronic pain 17 novel Schiff's bases, N,N'-(Z-allylidene-1,3-diyl)bisamino acid methyl esters were prepared from 1,1,3,3,-tetramethoxypropane and amino acid methyl esters. On tail-flick mouse model 20 micromol/kg of these Schiff's bases were orally administered, the analgesic action started 30 min after administration, reached the maximum 120 min after administration, and at 180 min this action was still observed. On a xylene-induced ear edema mouse model 20 micromol/kg of these Schiff's bases exhibited desirable anti-inflammation. Thus the present Schiff's bases are able to treat chronic pain from inflammation. The effect of the side chains of the amino acid residues of these Schiff's bases on the analgesic activity was explained with 3D QSAR.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Chronic Disease; Disease Models, Animal; Ear; Edema; Esters; Male; Mice; Mice, Inbred ICR; Models, Molecular; Molecular Structure; Pain; Quantitative Structure-Activity Relationship; Schiff Bases; Stereoisomerism; Xylenes

In this paper, we report the synthesis and pharmacological evaluation of pyrazine N-acylhydrazone (NAH) derivatives (2a-s) designed as novel analgesic and anti-inflammatory drug candidates. This series was planned by molecular simplification of prototype 1 (LASSBio-1018), previously described as a non-selective cyclooxygenase inhibitor. Derivatives 2a-s were evaluated in several animal models of pain and inflammation, standing-out compound 2o (2-N'-[(E)-(3,4,5-trimethoxyphenyl) methylidene]-2-pyrazinecarbohydrazide; LASSBio-1181), that was also active in a murine model of chronic inflammation (i.e., adjuvant-induced arthritis test in rats) and can be considered a new analgesic and anti-inflammatory lead for drug development.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Arthritis; Ear; Edema; Female; Freund's Adjuvant; Hydrazones; Male; Mice; Pain; Peritonitis; Pyrazines; Rats; Rats, Wistar; Zymosan

1,3-Disubstituted ureas possessing a piperidyl moiety have been synthesized to investigate their structure-activity relationships as inhibitors of the human and murine soluble epoxide hydrolase (sEH). Oral administration of 13 1-aryl-3-(1-acylpiperidin-4-yl)urea inhibitors in mice revealed substantial improvements in pharmacokinetic parameters over previously reported 1-adamantylurea based inhibitors. For example, 1-(1-(cyclopropanecarbonyl)piperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea (52) showed a 7-fold increase in potency, a 65-fold increase in C(max), and a 3300-fold increase in AUC over its adamantane analogue 1-(1-adamantyl)-3-(1-propionylpiperidin-4-yl)urea (2). This novel sEH inhibitor showed a 1000-fold increase in potency when compared to morphine by reducing hyperalgesia as measured by mechanical withdrawal threshold using the in vivo carrageenan induced inflammatory pain model.

Topics: Adamantane; Analgesics, Opioid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Epoxide Hydrolases; Humans; Male; Mice; Morphine; Pain; Piperidines; Rats; Rats, Sprague-Dawley; Solubility; Structure-Activity Relationship; Urea

Three isoforms of nitric oxide synthase (NOS), dimeric enzymes that catalyze the formation of nitric oxide (NO) from arginine, have been identified. Inappropriate or excessive NO produced by iNOS and/or nNOS is associated with inflammatory and neuropathic pain. Previously, we described the identification of a series of amide-quinolinone iNOS dimerization inhibitors that although potent, suffered from high clearance and limited exposure in vivo. By conformationally restricting the amide of this progenitor series, we describe the identification of a novel series of benzimidazole-quinolinone dual iNOS/nNOS inhibitors with low clearance and sustained exposure in vivo. Compounds were triaged utilizing an LPS challenge assay coupled with mouse and rhesus pharmacokinetics and led to the identification of 4,7-imidazopyrazine 42 as the lead compound. 42 (KD7332) (J. Med. Chem. 2009, 52, 3047 - 3062) was confirmed as an iNOS dimerization inhibitor and was efficacious in the mouse formalin model of nociception and Chung model of neuropathic pain, without showing tolerance after repeat dosing. Further 42 did not affect motor coordination up to doses of 1000 mg/kg, demonstrating a wide therapeutic margin.

Topics: Administration, Oral; Analgesics; Animals; Cell Line; Drug Tolerance; Fluoroquinolones; Humans; In Vitro Techniques; Mice; Microsomes, Liver; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Pain; Pain Measurement; Peripheral Nervous System Diseases; Protein Multimerization; Pyrazines; Rotarod Performance Test; Structure-Activity Relationship

Ten ester derivatives from caffeic acid were synthesized, and their antinociceptive properties are evaluated in mice. The most active compound, dodecyl ester derivative, exhibited potent and dose-related activity against the writhing test, with a calculated ID(50) value of 15.1 (11.9-19.1)micromol/kg and MI of 78.8% being several times more active than reference drugs. It was also effective in other experimental models, such as formalin, capsaicin and glutamate-induced pain tests, but was inactive in the hot-plate test. Although the mechanism of action has still not been elucidated, these results appear to support its therapeutic potential against painful diseases.

Topics: Analgesics; Animals; Caffeic Acids; Mice; Molecular Structure; Pain; Structure-Activity Relationship

Selective, nonpeptidic delta opioid receptor agonists have been the subject of great interest as potential novel analgesic agents. The discoveries of BW373U86 (1) and SNC80 (2) contributed to the rapid expansion of research in this field. However, poor drug-like properties and low therapeutic indices have prevented clinical evaluation of these agents. Doses of 1 and 2 similar to those required for analgesic activity produce convulsions in rodents and nonhuman primates. Recently, we described a novel series of potent, selective, and orally bioavailable delta opioid receptor agonists. The lead derivative, ADL5859 (4), is currently in phase II proof-of-concept studies for the management of pain. Further structure activity relationship exploration has led to the discovery of ADL5747 (36), which is approximately 50-fold more potent than 4 in an animal model of inflammatory pain. On the basis of its favorable efficacy, safety, and pharmacokinetic profile, 36 was selected as a clinical candidate for the treatment of pain.

Topics: Analgesics; Animals; Benzamides; Benzopyrans; CHO Cells; Clinical Trials as Topic; Cricetinae; Cricetulus; Crystallography, X-Ray; Cytochrome P-450 CYP2D6 Inhibitors; Dogs; Dose-Response Relationship, Drug; Drug Discovery; Ether-A-Go-Go Potassium Channels; Humans; Hyperalgesia; Male; Pain; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Spiro Compounds

Replacement of the phenyl ring in our previous (morpholinomethyl)aniline carboxamide cannabinoid receptor ligands with a pyridine ring led to the discovery of a novel chemical series of CB2 ligands. Compound 3, that is, 2,2-dimethyl-N-(5-methyl-4-(morpholinomethyl)pyridin-2-yl)butanamide was identified as a potent and selective CB2 agonist exhibiting in vivo efficacy after oral administration in a rat model of neuropathic pain.

Topics: Administration, Oral; Aminopyridines; Animals; Dogs; Humans; Male; Microsomes, Liver; Morpholines; Pain; Protein Binding; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Structure-Activity Relationship

A number of pyridazinone derivatives bearing an arylpiperazinylalkyl chain were synthesized and tested icv in a model of acute nociception induced by thermal stimuli in mice (tail flick). The most interesting and potent compound in this series was 6a, which showed an ED(50) = 3.5 microg, a value about 3-fold higher with respect to morphine by the same route of administration. When administered per os, 6a was 4-fold more potent than morphine in the same test, suggesting a significant bioavailability. The same compound also showed high potency in the hot plate test. The antinociceptive effect of 6a was completely reversed by pretreatment with yohimbine both in the hot plate test and in the tail flick test. This demonstrated the involvement of the adrenergic system, which was confirmed by in vitro radioligand binding studies.

Topics: Administration, Oral; Analgesics; Animals; Cell Line; Drug Discovery; Hot Temperature; Humans; Male; Mice; Pain; Piperazine; Piperazines; Pyridazines; Radioligand Assay; Rats; Receptors, Adrenergic; Structure-Activity Relationship

Fifteen different derivatives of an alpha- and beta-amyrin mixture were synthesized by acylation with appropriate anhydride or acid chlorides and oxidation in the presence of tert-butyl chromate or PCC. The molecular structures of the obtained compounds were confirmed by means of IR and (1)H NMR spectra. The compounds were screened for antinociceptive activity using the acetic acid pain model. The 3-O-acyl derivatives alpha- and beta-amyrin propionate 4, alpha- and beta-amyrin hexanoate 6, and alpha- and beta-amyrin octanoate 7 were found to be the most active compounds of the series. In addition, we also have found that alpha- and beta-amyrin octanoate 7 was able to reduce acetic acid-induced abdominal constriction when administered by oral route. Furthermore, this compound reduced the nociceptive response induced by intraplantar injection of formalin.

Topics: Analgesics; Animals; Disease Models, Animal; Mice; Molecular Structure; Oleanolic Acid; Pain; Structure-Activity Relationship; Triterpenes

Chiral tetrahydroquinoline derivatives have been prepared by an asymmetric Mannich-type condensation reaction using commercially available vinyloxyethylsilane and a N-arylimino R-(+)-t-butyl lactate ester, in the presence of a catalytic amount of metal triflates as Lewis acids. This synthetic approach gave rise to the target aldehyde intermediate in moderate facial diastereoselectivity and in high chemical yield. This efficient route enabled to scale up the synthesis of an orally bioavailable glycine antagonist showing outstanding in vivo anti-hyperalgesic activity in different animal models of sustained inflammation and chronic neuropathic pain.

Topics: Animals; Biological Availability; Disease Models, Animal; Glycine; Hydroquinones; Hyperalgesia; Inflammation; Pain; Rats; Stereoisomerism; Structure-Activity Relationship

Sickle cell anemia is a common genetic disorder in African Americans. Opioid analgesics are traditionally the treatment for the severe pain associated with this disease. Here we reveal that the opioid antagonist naloxone possesses potent analgesic activity in two transgenic mouse models of sickle cell anemia (NY1DD and hBERK1) and not in their respective controls (ICR-CD1 and C57BL/6J) when administered by three parenteral routes [intracerebroventricular (i.c.v.), intrathecal, and subcutaneous]. In the NY1DD mice, naloxone (i.c.v.) possessed approximately 300-fold greater potency than morphine (i.c.v.). Other opioid antagonists (naltrexone, norbinaltorphimine, and naltrindole) were substantially less effective in producing analgesia. Naloxone and morphine were synergistic in NY1DD mice, suggesting different receptor systems. Microarray analysis suggested naloxone-induced down-regulation of the CC chemokine receptor (CCR)5 in NY1DD mice but not in control mice. Pretreatment of control mice with CC chemokine ligand 5 [CCL5 (RANTES)] enabled naloxone to produce analgesia similar to that observed in NY1DD mice. Mu opioid receptor knockout mice treated similarly also displayed analgesia. That the effect of CCL5 was specifically related to CCR5 and/or CCR1 activation was demonstrated by antagonism of analgesia with the chemokine antagonist methionylated RANTES. Similar antagonism of naloxone-induced analgesia also was observed when NY1DD mice were pretreated with methionylated RANTES. These results indicate that CCR5/CCR1 receptors are directly or indirectly involved in analgesia produced by naloxone. The present study suggests that naloxone may be clinically useful in the treatment of pain associated with sickle cell disease and other disorders involving inflammation.

Topics: Analgesics; Analgesics, Opioid; Anemia, Sickle Cell; Animals; Chemokine CCL5; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Drug Synergism; Injections, Intraventricular; Injections, Spinal; Injections, Subcutaneous; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Transgenic; Morphine; Naloxone; Pain; Pain Measurement; Receptors, CCR5

The 2',6'-dimethyl-l-tyrosine (Dmt) enhances receptor affinity, functional bioactivity and in vivo analgesia of opioid peptides. To further investigate its direct influence on these opioid parameters, we developed a series of compounds (H-Dmt-NH-X). Among them, H-Dmt-NH-CH(3) showed the highest affinity (K(i)mu=7.45 nM) equal to that of morphine, partial mu-opioid agonism (E(max)=66.6%) in vitro and a moderate antinociception in mice.

Topics: Analgesics; Animals; Dose-Response Relationship, Drug; Guinea Pigs; Ilium; Ligands; Male; Mice; Pain; Radioligand Assay; Receptors, Opioid, delta; Receptors, Opioid, mu; Structure-Activity Relationship; Tyrosine; Vas Deferens

Several compounds with a 4-aminopiperidine scaffold decorated on both nitrogen atoms by alkyl or acyl moieties containing the structural motifs of verapamil and of flunarizine, as well as those that are more frequent in known N-type calcium channel antagonists, have been synthesized. Antinociceptive activity on the mouse hot-plate test was used to select molecules to be submitted to further studies. Active compounds were tested in vitro on a PC12 rat pheochromocytoma clonal cell line, to evaluate their action on N-type calcium channels, and on a rat model of neuropathic pain. Two compounds that show N-type calcium channel antagonism and are endowed with potent action on pain and neuropathic pain (3 and 18) have been selected for further studies.

Topics: Analgesics; Animals; Binding Sites; Butanones; Calcium; Calcium Channel Blockers; Calcium Channels, N-Type; Cerebral Ventricles; Drug Design; In Vitro Techniques; Male; Mice; Pain; Pain Measurement; Pain Threshold; PC12 Cells; Peripheral Nervous System Diseases; Piperidines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship

A number of [(3-chlorophenyl)piperazinylpropyl]pyridazinones and the corresponding isoxazolopyridazinones, showing the arylpiperazinyl substructure present in very potent antinociceptive agents reported in the literature, were synthesized and tested for their analgesic activity. The investigated compounds showed antinociceptive properties in the mouse hot-plate test (thermal nociceptive stimulus) after systemic administration with an efficacy similar to that exerted by morphine. The increase of the pain threshold induced by the compounds labeled 5a, 7, 8, and 11 was prevented by reserpine, suggesting the involvement of the noradrenergic and/or serotoninergic system in their mechanism of action. Among them, 7 and 11 showed the highest analgesic potency and efficacy together with a good ratio (133 and 200, respectively) of the minimal nontoxic dose (MNTD) to the minimal analgesic dose (MAD). Furthermore, they were also active after icv administration and in the presence of a chemical, painful stimulus (abdominal constriction test).

Topics: Abdominal Muscles; Acetic Acid; Analgesics; Animals; Dose-Response Relationship, Drug; Injections, Intraventricular; Injections, Subcutaneous; Male; Mice; Muscle Contraction; Pain; Pain Measurement; Pain Threshold; Piperazines; Pyridazines; Structure-Activity Relationship

The solid phase procedure, based on the Fmoc chemistry, was used to prepare some opioid deltorphin (H-Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2, DEL C) and dermorphin (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2, DER) analogues in which a D-glucopyranosyl moiety is beta-O-glycosidically linked to a Thr4 or Thr7 side chain. Their activities were determined in binding studies based on displacement of mu- and delta-receptor selective radiolabels from rat brain membrane synaptosomes, in guinea pig ileum and rabbit jejenum bioassays, and, in vivo, by a mouse tail-flick test after intracerebroventricular (icv) and subcutaneous (sc) administrations. The glyco analogues modified at position 4 displayed low opioid properties, while Thr7-glycosylated peptides retained high delta- or mu-selectivity and remarkable activity in vivo. In particular, as systemic antinociceptive agents, the latter glucoside-bearing compounds were more potent than the parent unglycosylated peptide counterparts, showing a high blood to brain rate of influx which may be due to the glucose transporter GLUT-1.

Topics: Amino Acid Sequence; Analgesics, Opioid; Animals; Binding, Competitive; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Glycopeptides; Guinea Pigs; Ileum; In Vitro Techniques; Indicators and Reagents; Jejunum; Kinetics; Male; Mice; Muscle Contraction; Muscle, Smooth; Oligopeptides; Opioid Peptides; Pain; Rabbits; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Structure-Activity Relationship; Synaptosomes

A series of trans-3-(6- and 7-substituted-decahydro-4a-isoquinolinyl)phenols and trans-3-(octahydro-4a-isoquinolinyl)phenols have been synthesized as potential opioid analgesics. Using a combination of in vitro and in vivo test systems, the receptor profiles of selected compounds have been assessed and in some instances distinguish between mu- and kappa-receptor agonists. In general, introduction of a 6-exocyclic methylene group into the trans-3-(decahydro-4a-isoquinolinyl)phenol system enhanced both antinociceptive activity and kappa-opioid receptor selectivity. For each series, analogues bearing an N-cyclopropylmethyl substituent exhibited greater kappa-receptor selectivity while N-methyl derivatives showed greater mu-receptor selectivity. The 7-substituted compounds (3b) were significantly less potent antinociceptive agents than their 6-substituted counterparts (3a), the octahydroisoquinoline analogues exhibiting intermediate activity. The axial 8-methyl-6-exocyclic methylene isoquinoline (20) is the most potent compound in the mouse abdominal constriction assay (ED50 = 0.05 mg/kg sc), whereas the equatorial 8-methyl isomer (16) was significantly less potent (ED50 = 3.3 mg/kg sc).

Topics: Analgesics; Animals; Guinea Pigs; Isoquinolines; Male; Mice; Pain; Phenols; Rabbits; Receptors, Opioid; Stereoisomerism; Structure-Activity Relationship

The synthesis and analgesic testing of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]cyclohexanol (1) are described. Prior (SAR) studies led us to conclude that the pyran ring of 9-nor-9 beta-hydroxyhexahydrocannabinol (HHC) was not necessary for the expression of biological activity in this series of cannabinoids. Analysis of models and the use of molecular mechanics calculations suggested that a simpler compound, such as 1, would possess the biological activity of HHC. Compound 1 was prepared in nine steps from [3-(benzyloxy)phenyl]acetonitrile (2). Biological testing in five models of pain shows that compound 1 and morphine are equally potent as analgesics and demonstrates that the pyran ring of HHC is not necessary for biological activity. Further simplification of 1 was pursued by the synthesis of 4-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-2-pentanol (17), but this derivative exhibits significantly reduced analgesic activity.

Topics: Analgesics; Animals; Cannabinoids; Cyclohexanols; Dogs; Drug Evaluation, Preclinical; Indicators and Reagents; Magnetic Resonance Spectroscopy; Mice; Models, Molecular; Pain; Rats; Spectrophotometry, Infrared; Structure-Activity Relationship

A series of 5-aryl-2-azabicyclo[3.2.1]octanes II has been synthesized and evaluated for analgetic agonist-antagonist activity. These compounds can be regarded as five-membered, conformationally more rigid analogues of the potent agonist-antagonist (-)-5-(3-hydroxyphenyl)-2-methylmorphan (I). Several of these compounds have demonstrated marked analgesic potency comparable to morphine in the mouse writhing assay. Structure-activity correlations, generated by varying N-substitution and O-acetylation of the phenolic function, seem to indicate that optimum activity is associated with an arylethyl side chain attached to the basic nitrogen. Among the most interesting compounds in this series are the phenethyl analogue 31 and its O-acetate 39; the former shows the profile of a well-balanced analgetic-antagonist virtually devoid of physical dependence liability as demonstrated in the rat infusion test.

Topics: Analgesics; Animals; Aza Compounds; Bridged Bicyclo Compounds; Bridged-Ring Compounds; Mice; Molecular Conformation; Pain; Quinones; Reaction Time; Structure-Activity Relationship

Twelve patients with meconium ileus equivalent complicating cystic fibrosis in the postneonatal period were seen at the Mayo Clinic in the years 1950 through 1975. In a child or young adult with known or suspected cystic fibrosis, the triad of recurrent colicky abdominal pain, a mass in the right lower quadrant, and mechanical intestinal obstruction provides a clue to diagnosis of meconium ileus equivalent. The clinical suspicion of meconium ileus equivalent may be confirmed by meglumine diatrizoate (Gastrografin) enema, which in most uncomplicated cases also serves as treatment.

Topics: Adolescent; Adult; Barium Sulfate; Child; Child, Preschool; Cystic Fibrosis; Diatrizoate Meglumine; Enema; Female; Humans; Infant; Intestinal Obstruction; Male; Meconium; Minnesota; Pain

Topics: Abdomen; Adolescent; Anemia; Child; Child, Preschool; Constipation; Diagnosis, Differential; Female; Guaiac; Humans; Infant, Newborn; Male; Meconium; Megacolon; Melena; Neuromuscular Diseases; Pain; Pediatrics; Posture; Rectal Diseases; Rectum; Sigmoidoscopy; Urethral Diseases; Vaginal Diseases