ABSTRACT
The lack of selective pharmacological tools has limited the full unraveling of G protein-coupled receptor 18 (GPR18) functions. The present study was aimed at discovering the activities of three novel preferential or selective GPR18 ligands, one agonist (PSB-KK-1415) and two antagonists (PSB-CB-5 and PSB-CB-27). We investigated these ligands in several screening tests, considering the relationship between GPR18 and the cannabinoid (CB) receptor system, and the control of endoCB signaling over emotions, food intake, pain sensation, and thermoregulation. We also assessed whether the novel compounds could modulate the subjective effects evoked by Δ9-tetrahydrocannabinol (THC). Male mice or rats were pretreated with the GPR18 ligands, and locomotor activity, depression- and anxiety-like symptoms, pain threshold, core temperature, food intake, and THC-vehicle discrimination were measured. Our screening analyses indicated that GPR18 activation partly results in effects that are similar to those of CB receptor activation, considering the impact on emotional behavior, food intake, and pain activity. Thus, the orphan GPR18 may provide a novel therapeutic target for mood, pain, and/or eating disorders, and further investigation is warranted to better discern its function.
Subject(s)
Feeding and Eating Disorders , Rodentia , Rats , Male , Mice , Animals , Ligands , Pain/drug therapy , Receptors, Cannabinoid , Dronabinol/pharmacology , Receptor, Cannabinoid, CB1 , Dose-Response Relationship, Drug , Receptors, G-Protein-CoupledABSTRACT
BACKGROUND: Neuropathic pain is drug-resistant to available analgesics and therefore novel treatment options for this debilitating clinical condition are urgently needed. Recently, two drug candidates, namely mirogabalin and cebranopadol have become a subject of interest because of their potential utility as analgesics for chronic pain treatment. However, they have not been investigated thoroughly in some types of neuropathic pain, both in humans and experimental animals. METHODS: This study used the von Frey test, the hot plate test and the two-plate thermal place preference test supported by image analysis and machine learning to assess the effect of intraperitoneal mirogabalin and subcutaneous cebranopadol on mechanical and thermal nociceptive threshold in mouse models of neuropathic pain induced by streptozotocin, paclitaxel and oxaliplatin. RESULTS: Mirogabalin and cebranopadol effectively attenuated tactile allodynia in models of neuropathic pain induced by streptozotocin and paclitaxel. Cebranopadol was more effective than mirogabalin in this respect. Both drugs also elevated the heat nociceptive threshold in mice. In the oxaliplatin model, cebranopadol and mirogabalin reduced cold-exacerbated pain. CONCLUSIONS: Since mirogabalin and cebranopadol are effective in animal models of neuropathic pain, they seem to be promising novel therapies for various types of neuropathic pain in patients, in particular those who are resistant to available analgesics.
Subject(s)
Neuralgia , Nociception , Mice , Humans , Animals , Oxaliplatin/therapeutic use , Streptozocin , Analgesics/pharmacology , Analgesics/therapeutic use , Neuralgia/drug therapy , Paclitaxel/pharmacology , Paclitaxel/therapeutic useABSTRACT
Despite advances in antimicrobial and anti-inflammatory therapies, inflammation and its consequences still remain a significant problem in medicine. Acute inflammatory responses are responsible for directly life-threating conditions such as septic shock; on the other hand, chronic inflammation can cause degeneration of body tissues leading to severe impairment of their function. Neuroinflammation is defined as an inflammatory response in the central nervous system involving microglia, astrocytes, and cytokines including chemokines. It is considered an important cause of neurodegerative diseases, such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Lipopolysaccharide (LPS) is a strong immunogenic particle present in the outer membrane of Gram-negative bacteria. It is a major triggering factor for the inflammatory cascade in response to a Gram-negative bacteria infection. The use of LPS as a strong pro-inflammatory agent is a well-known model of inflammation applied in both in vivo and in vitro studies. This review offers a summary of the pathogenesis associated with LPS exposure, especially in the field of neuroinflammation. Moreover, we analyzed different in vivo LPS models utilized in the area of neuroscience. This paper presents recent knowledge and is focused on new insights in the LPS experimental model.
Subject(s)
Lipopolysaccharides , Neuroinflammatory Diseases , Cytokines , Humans , Inflammation/pathology , Lipopolysaccharides/adverse effects , Microglia/pathologyABSTRACT
Trying to meet the multitarget-directed ligands strategy, a series of previously described aryl-substituted phenylalanine derivatives, reported as competitive antagonists of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, were screened in vitro for their free-radical scavenging and antioxidant capacity in two different assays: ferric reducing antioxidant power (FRAP) and oxygen radical absorbance capacity fluorescent (ORAC-FL) assays. The most active antioxidants 1 and 8 were further examined to evaluate their neuroprotective properties in vitro. In this study, compound 1 showed a significant neuroprotective effect against the neurotoxin 6-hydroxydopamine in neuroblastoma SH-SY5Y and IMR-32 cell lines. Both compounds also showed prevention from high levels of reactive oxygen species (ROS) in SH-SY5Y cells. Furthermore, the desired monoamine oxidase B (MAO-B) inhibition effect (IC50 = 278 ± 29 nM) for 1 was determined. No toxic effects up to 100 µM of 1 and 8 against neuroblastoma cells were observed. Furthermore, in vivo studies showed that compound 1 demonstrated significant anticonvulsant potential in 6-Hz test, but in neuropathic pain models its antiallodynic and antihyperalgesic properties were not observed. Concluding, the compound 1 seems to be of higher importance as a new phenylalanine-based lead candidate due to its confirmed promise in in vitro and in vivo anticonvulsant activity.
Subject(s)
Anticonvulsants , Monoamine Oxidase Inhibitors , Monoamine Oxidase/metabolism , Neuroprotective Agents , Phenylalanine , Receptors, AMPA/antagonists & inhibitors , Animals , Anticonvulsants/chemical synthesis , Anticonvulsants/chemistry , Anticonvulsants/pharmacology , Cell Line, Tumor , Humans , Male , Mice , Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/pharmacology , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacology , Oxidopamine/toxicity , Phenylalanine/analogs & derivatives , Phenylalanine/chemical synthesis , Phenylalanine/chemistry , Phenylalanine/pharmacology , Receptors, AMPA/metabolismABSTRACT
A focused library of new 3-(3-methyl-2,5-dioxo-3-phenylpyrrolidin-1-yl)propanamides and their nonimide analogs were synthesized and tested for anticonvulsant activity. These compounds were obtained through the coupling reaction of the starting carboxylic acids with appropriate amines. The initial anticonvulsant screening was performed in mice (intraperitoneal administration) using the maximal electroshock seizure (MES) and the subcutaneous pentylenetetrazole (scPTZ) seizure models. The most promising compound 6 showed more potent protection in the MES and scPTZ tests than valproic acid, which is still recognized as one of the most relevant first-line anticonvulsants. The structure-activity relationship analysis revealed that the presence of the pyrrolidine-2,5-dione ring is important but not indispensable to retain anticonvulsant activity. Additionally, compound 6 showed potent antinociceptive properties in the oxaliplatin-induced neuropathic pain model in mice. The most plausible mechanism of action for compound 6 may result from its influence on the neuronal sodium channel (Site 2) and the high-voltage-activated L-type calcium channel.
Subject(s)
Amides/pharmacology , Analgesics/pharmacology , Anticonvulsants/pharmacology , Amides/chemical synthesis , Amides/chemistry , Analgesics/chemical synthesis , Analgesics/chemistry , Animals , Anticonvulsants/chemical synthesis , Anticonvulsants/chemistry , Disease Models, Animal , Electroshock , Male , Mice , Pain/drug therapy , Pentylenetetrazole , Seizures/drug therapy , Structure-Activity Relationship , Valproic Acid/pharmacologyABSTRACT
Fibromyalgia is a disease characterized by lowered pain threshold, mood disorders, and decreased muscular strength. It results from a complex dysfunction of the nervous system and due to unknown etiology, its diagnosis, treatment, and prevention are a serious challenge for contemporary medicine. Impaired serotonergic and dopaminergic neurotransmission are regarded as key factors contributing to fibromyalgia. The present research assessed the effect of serotonergic and dopaminergic system modulators (vortioxetine and ropinirole, respectively) on the pain threshold, depressive-like behavior, anxiety, and motor functions of mice with fibromyalgia-like symptoms induced by subcutaneous reserpine (0.25 mg/kg). By depleting serotonin and dopamine in the mouse brain, reserpine induced symptoms of human fibromyalgia. Intraperitoneal administration of vortioxetine and ropinirole at the dose of 10 mg/kg alleviated tactile allodynia. At 5 and 10 mg/kg ropinirole showed antidepressant-like properties, while vortioxetine had anxiolytic-like properties. None of these drugs influenced muscle strength but reserpine reduced locomotor activity of mice. Concluding, in the mouse model of fibromyalgia vortioxetine and ropinirole markedly reduced pain. These drugs affected emotional processes of mice in a distinct manner. Hence, these two repurposed drugs should be considered as potential drug candidates for fibromyalgia. The selection of a specific drug should depend on patient's key symptoms.
Subject(s)
Dopamine Agonists/pharmacology , Fibromyalgia/drug therapy , Indoles/pharmacology , Pain/drug therapy , Vortioxetine/pharmacology , Animals , Disease Models, Animal , Dopamine/genetics , Fibromyalgia/genetics , Fibromyalgia/pathology , Humans , Mice , Pain/genetics , Pain/pathology , Pain Threshold , Receptors, Dopamine D2/agonists , Receptors, Dopamine D3/agonists , Serotonin/genetics , Synaptic Transmission/drug effectsABSTRACT
The antitumor drug, oxaliplatin, induces neuropathic pain, which is resistant to available analgesics, and novel mechanism-based therapies are being evaluated for this debilitating condition. Since activated microglia, impaired serotonergic and noradrenergic neurotransmission and overexpressed sodium channels are implicated in oxaliplatin-induced pain, this in vivo study assessed the effect of minocycline, a microglial activation inhibitor used alone or in combination with ambroxol, a sodium channel blocker, or duloxetine, a serotonin and noradrenaline reuptake inhibitor, on oxaliplatin-induced tactile allodynia and cold hyperalgesia. To induce neuropathic pain, a single dose (10 mg/kg) of intraperitoneal oxaliplatin was used. The mechanical and cold pain thresholds were assessed using mouse von Frey and cold plate tests, respectively. On the day of oxaliplatin administration, only duloxetine (30 mg/kg) and minocycline (100 mg/kg) used alone attenuated both tactile allodynia and cold hyperalgesia 1 h and 6 h after administration. Minocycline (50 mg/kg), duloxetine (10 mg/kg) and combined minocycline + duloxetine influenced only tactile allodynia. Seven days after oxaliplatin, tactile allodynia (but not cold hyperalgesia) was attenuated by minocycline (100 mg/kg), duloxetine (30 mg/kg) and combined minocycline and duloxetine. These results indicate a potential usefulness of minocycline used alone or combination with duloxetine in the treatment of oxaliplatin-induced pain.
Subject(s)
Duloxetine Hydrochloride/pharmacology , Microglia/drug effects , Minocycline/pharmacology , Neuralgia/drug therapy , Oxaliplatin/toxicity , Pain Threshold/drug effects , Analgesics/pharmacology , Animals , Anti-Bacterial Agents/pharmacology , Antineoplastic Agents/toxicity , Behavior, Animal/drug effects , Disease Models, Animal , Drug Combinations , Male , Mice , Microglia/physiology , Neuralgia/chemically induced , Neuralgia/pathologyABSTRACT
BACKGROUND: Wide use of oxaliplatin as an antitumor drug is limited by severe neuropathy with pharmacoresistant cold hypersensitivity as the main symptom. Novel analgesics to attenuate cold hyperalgesia and new methods to detect drug candidates are needed. METHODS: We developed a method to study thermal preference of oxaliplatin-treated mice and assessed analgesic activity of intraperitoneal duloxetine and pregabalin used at 30 mg/kg. A prototype analgesiameter and a broad range of temperatures (0-45 °C) were used. Advanced methods of image analysis (deep learning and machine learning) enabled us to determine the effectiveness of analgesics. The loss or reversal of thermal preference of oxaliplatin-treated mice was a measure of analgesia. RESULTS: Duloxetine selectively attenuated cold-induced pain at temperatures between 0 and 10 °C. Pregabalin-treated mice showed preference towards a colder plate of the two used at temperatures between 0 and 45 °C. CONCLUSION: Unlike duloxetine, pregabalin was not selective for temperatures below thermal preferendum. It influenced pain sensation at a much wider range of temperatures applied. Therefore, for the attenuation of cold hypersensitivity duloxetine seems to be a better than pregabalin therapeutic option. We propose wide-range measurements of thermal preference as a novel method for the assessment of analgesic activity in mice.
Subject(s)
Analgesics/pharmacology , Hyperalgesia/drug therapy , Pain/drug therapy , Animals , Antineoplastic Agents/pharmacology , Cold Temperature , Disease Models, Animal , Duloxetine Hydrochloride/pharmacology , Hot Temperature , Male , Mice , Oxaliplatin/pharmacology , Pain Measurement/methods , Pregabalin/pharmacology , TemperatureABSTRACT
Tiagabine is an antiepileptic drug used for the treatment of partial seizures in humans. Recently, this drug has been found useful in several non-epileptic conditions, including anxiety, chronic pain and sleep disorders. Since tachycardia-an impairment of cardiac rhythm due to cardiac ion channel dysfunction-is one of the most commonly reported non-neurological adverse effects of this drug, in the present paper we have undertaken pharmacological and numerical studies to assess a potential cardiovascular risk associated with the use of tiagabine. A chemical interaction of tiagabine with a model of human voltage-gated ion channels (VGICs) is described using the molecular docking method. The obtained in silico results imply that the adverse effects reported so far in the clinical cardiological of tiagabine could not be directly attributed to its interactions with VGICs. This is also confirmed by the results from the isolated organ studies (i.e., calcium entry blocking properties test) and in vivo (electrocardiogram study) assays of the present research. It was found that tachycardia and other tiagabine-induced cardiac complications are not due to a direct effect of this drug on ventricular depolarization and repolarization.
Subject(s)
Calcium Channels, L-Type/chemistry , ERG1 Potassium Channel/antagonists & inhibitors , Epilepsy/drug therapy , Heart/drug effects , NAV1.5 Voltage-Gated Sodium Channel/chemistry , Tiagabine/pharmacology , Action Potentials , Animals , Anticonvulsants/adverse effects , Calcium Channels, L-Type/metabolism , Computer Simulation , ERG1 Potassium Channel/metabolism , Epilepsy/complications , Epilepsy/metabolism , Humans , Male , Molecular Docking Simulation/methods , NAV1.5 Voltage-Gated Sodium Channel/metabolism , Rats , Rats, Wistar , Tiagabine/adverse effectsABSTRACT
As part of the presented research, thirteen new aminoalkanol derivatives were designed and obtained by chemical synthesis. In vivo studies (mice, i.p.) showed anticonvulsant activity (MES) of nine compounds, and in the case of one compound (R,S-trans-2-((2-(2,3,5-trimethylphenoxy)ethyl)amino)cyclohexan-1-ol, 4) both anticonvulsant (ED50 MES = 15.67 mg/kg, TD50 rotarod = 78.30 mg.kg, PI = 5.00) and analgesic activity (OXA-induced neuropathic pain, active at 15 mg/kg). For selected active compounds additional in vitro studies have been performed, including receptor studies (5-HT1A), evaluation of antioxidant activity (DPPH assay), metabolism studies as well as safety panel (mutagenicity, safety in relation to the gastrointestinal flora, cytotoxicity towards astrocytes as well as impact on their proliferation and cell cycle).
Subject(s)
Amino Alcohols/pharmacology , Analgesics/pharmacology , Anticonvulsants/pharmacology , Antioxidants/pharmacology , Neuralgia/drug therapy , Amino Alcohols/chemistry , Analgesics/chemistry , Analgesics/metabolism , Animals , Anticonvulsants/chemistry , Anticonvulsants/metabolism , Antioxidants/chemistry , Antioxidants/metabolism , Biphenyl Compounds/antagonists & inhibitors , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Humans , Molecular Structure , Picrates/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
Recent progress in the field of neurobiology supported by clinical evidence gradually reveals the mystery of human brain functioning. So far, many psychiatric disorders have been described in great detail, although there are still plenty of cases that are misunderstood. These include posttraumatic stress disorder (PTSD), which is a unique disease that combines a wide range of neurobiological changes, which involve disturbances of the hypothalamic-pituitary-adrenal gland axis, hyperactivation of the amygdala complex, and attenuation of some hippocampal and cortical functions. Such multiplicity results in differential symptomatology, including elevated anxiety, nightmares, fear retrieval episodes that may trigger delusions and hallucinations, sleep disturbances, and many others that strongly interfere with the quality of the patient's life. Because of widespread neurological changes and the disease manifestation, the pharmacotherapy of PTSD remains unclear and requires a multidimensional approach and involvement of polypharmacotherapy. Hopefully, more and more neuroscientists and clinicians will study PTSD, which will provide us with new information that would possibly accelerate establishment of well-tolerated and effective pharmacotherapy. In this review, we have focused on neurobiological changes regarding PTSD, addressing the most disturbed brain structures and neurotransmissions, as well as discussing in detail the recently taken and novel therapeutic paths.
Subject(s)
Stress Disorders, Post-Traumatic , Animals , Brain/metabolism , Brain/pathology , Humans , Hypothalamo-Hypophyseal System , Neurosteroids/metabolism , Pituitary-Adrenal System , Stress Disorders, Post-Traumatic/drug therapy , Stress Disorders, Post-Traumatic/metabolism , Stress Disorders, Post-Traumatic/pathologyABSTRACT
The aim of this study was to design and synthesize two series of N-Mannich bases with imidazolidine-2,4-dione core as a potential anticonvulsant with reduced toxicity and broad antiseizure activity. Preliminary screening revealed that the majority of synthesized compounds were effective in the maximal electroshock seizure (MES) and/or subcutaneous pentylenetetrazole (scPTZ) test. The most active in vivo compound, 18 (3-((4-methylpiperazin-1-yl)methyl)-5,5-diphenylimidazolidine-2,4-dione), exhibited an ED50 value comparable to that of phenytoin in the MES test (38.5â¯mg/kg vs 28.1â¯mg/kg), and more importantly, it showed four times higher potency than phenytoin in the 6â¯Hz test (12.2â¯mg/kg vsâ¯>â¯60â¯mg/kg). Additionally, 18 exhibited antiallodynic properties in the von Frey test in neuropathic (oxaliplatin-treated) mice. Compound 18 also demonstrated a broader spectrum of anticonvulsant activity than phenytoin and showed statistically significant antinociceptive properties in selected models of chronic pain.
Subject(s)
Anticonvulsants/therapeutic use , Imidazolidines/therapeutic use , Mannich Bases/therapeutic use , Pain/drug therapy , Seizures/drug therapy , Animals , Anticonvulsants/administration & dosage , Anticonvulsants/chemical synthesis , Disease Models, Animal , Dose-Response Relationship, Drug , Imidazolidines/administration & dosage , Imidazolidines/chemical synthesis , Mannich Bases/administration & dosage , Mannich Bases/chemical synthesis , Mice , Molecular Structure , Oxaliplatin , Pain/chemically induced , Rats , Seizures/chemically induced , Structure-Activity RelationshipABSTRACT
In the search for new treatments for complex disorders such as Alzheimer's disease the Multi-Target-Directed Ligands represent a very promising approach. The aim of the present study was to identify multifunctional compounds among several series of non-imidazole histamine H3 receptor ligands, derivatives of 1-[2-thiazol-5-yl-(2-aminoethyl)]-4-n-propylpiperazine, 1-[2-thiazol-4-yl-(2-aminoethyl)]-4-n-propylpiperazine and 1-phenoxyalkyl-4-(amino)alkylopiperazine using in vitro and in vivo pharmacological evaluation and computational studies. Performed in vitro assays showed moderate potency of tested compounds against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Molecular modeling studies have revealed possible interactions between the active compounds and both AChE and BuChE as well as the human H3 histamine receptor. Computational studies showed the high drug-likeness of selected compounds with very good physicochemical profiles. The parallel artificial membrane permeation assay proved outstanding blood-brain barrier penetration in test conditions. The most promising compound, A12, chemically methyl(4-phenylbutyl){2-[2-(4-propylpiperazin-1-yl)-1,3-thiazol-5-yl]ethyl}amine, possesses good balanced multifunctional profile with potency toward studied targets - H3 antagonist activity (pA2â¯=â¯8.27), inhibitory activity against both AChE (IC50â¯=â¯13.96⯵M), and BuChE (IC50â¯=â¯14.62⯵M). The in vivo pharmacological studies revealed the anti-amnestic properties of compound A12 in the passive avoidance test on mice.
Subject(s)
Alzheimer Disease/drug therapy , Amnesia/drug therapy , Cholinesterase Inhibitors/pharmacology , Disease Models, Animal , Piperazines/chemistry , Receptors, Histamine H3/metabolism , Acetylcholinesterase/chemistry , Adjuvants, Anesthesia/toxicity , Amnesia/chemically induced , Animals , Butyrylcholinesterase/chemistry , Cholinesterase Inhibitors/chemistry , Computational Biology , In Vitro Techniques , Ligands , Male , Mice , Models, Molecular , Molecular Structure , Receptors, Histamine H3/chemistry , Scopolamine/toxicity , Structure-Activity RelationshipABSTRACT
Aim of the study was evaluation of anxiolytic, antidepressant, anticonvulsant and analgesic activity in a series of a consistent group of compounds. A series of eleven new N-(phenoxyalkyl)- or N-{2-[2-(phenoxy)ethoxy]ethyl}piperazine derivatives has been obtained. Their affinity towards 5-HT1A, 5-HT2A, 5-HT6, 5-HT7, D2 and α1 receptors has been assessed, and then functional assays were performed. The compounds were evaluated in mice, i.p. for their antidepressant-like (forced swim test), locomotor, anxiolytic-like (four-plate test) activities as well as - at higher doses - for anticonvulsant potential (MES) and neurotoxicity (rotarod). Two compounds (3, 6) were also evaluated for their analgesic activity in neuropathic pain models (streptozocin test, oxaliplatin test) and they were found active against allodynia in diabetic neuropathic pain at 30â¯mg/kg. Among the compounds, anxiolytic-like, anticonvulsant or analgesic activity was observed but antidepressant-like activity was not. One of the two most interesting compounds is 1-{2-[2-(2,4,6-trimethylphenoxy)ethoxy]ethyl}-4-(2-methoxyphenyl)piperazine dihydrochloride (9), exhibiting anxiolytic and anticonvulsant activity in mice, i.p. 30 min after administration (at 2.5â¯mg/kg and ED50â¯=â¯26.33â¯mg/kg, respectively), which can be justified by the receptor profile: 5-HT1A Kiâ¯=â¯5â¯nM (antagonist), 5-HT7 Kiâ¯=â¯70â¯nM, α1 Kiâ¯=â¯15â¯nM, D2 Kiâ¯=â¯189â¯nM (antagonist). Another interesting compound is 1-[3-(2,4,6-trimethylphenoxy)propyl]-4-(4-methoxyphenyl)piperazine dihydrochloride (3), exhibiting anxiolytic, anticonvulsant and antiallodynic activity in mice, i.p., 30â¯min after administration (at 10â¯mg/kg, ED50â¯=â¯23.50â¯mg/kg, at 30â¯mg/kg, respectively), which can be related with 5-HT1A weak antagonism (Kiâ¯=â¯146â¯nM), or other possible mechanism of action, not evaluated within presented study. Additionally, for the most active compound in the four-plate test (7), molecular modeling was performed (docking to receptors 5-HT1A, 5-HT2A, 5-HT7, D2 and α1A).
Subject(s)
Anticonvulsants/pharmacology , Central Nervous System/drug effects , Motor Activity/drug effects , Piperazine/pharmacology , Receptors, Serotonin/metabolism , Serotonin Receptor Agonists/pharmacology , Animals , Anticonvulsants/administration & dosage , Anticonvulsants/chemistry , Central Nervous System/metabolism , Dose-Response Relationship, Drug , Injections, Intraperitoneal , Mice , Models, Molecular , Molecular Structure , Piperazine/administration & dosage , Piperazine/chemistry , Serotonin Receptor Agonists/administration & dosage , Serotonin Receptor Agonists/chemistry , Structure-Activity RelationshipABSTRACT
BACKGROUND: Cebranopadol (a.k.a. GRT-6005) is a dually acting nociceptin/orphanin FQ and opioid receptor agonist that has been recently developed in Phase 2 clinical trials for painful diabetic neuropathy or cancer pain. It also showed analgesic properties in various rat models of pain and had a better safety profile as compared to equi-analgesic doses of morphine. Since antinociceptive properties of cebranopadol have been studied mainly in rat models, in the present study, we assessed analgesic activity of subcutaneous cebranopadol (10 mg/kg) in various mouse pain models. METHODS: We used models of acute, tonic, and chronic pain induced by thermal and chemical stimuli, with a particular emphasis on pharmacoresistant chronic neuropathic pain evoked by oxaliplatin in which cebranopadol was used alone or in combination with simvastatin. KEY RESULTS: As shown in the hot plate test, the analgesic activity of cebranopadol developed more slowly as compared to morphine (90-120 min vs. 60 min). Cebranopadol displayed a significant antinociceptive activity in acute pain models, i.e., the hot plate, writhing, and capsaicin tests. It attenuated nocifensive responses in both phases of the formalin test and reduced cold allodynia in oxaliplatin-induced neuropathic pain model. Its efficacy was similar to that of morphine. Used in combination and administered simultaneously, 4 or 6 h after simvastatin, cebranopadol did not potentiate antiallodynic activity of this cholesterol-lowering drug. Cebranopadol did not induce any motor deficits in the rotarod test. CONCLUSION: Cebranopadol may have significant potential for the treatment of various pain types, including inflammatory and chemotherapy-induced neuropathic pain.
Subject(s)
Analgesics, Opioid/pharmacology , Indoles/pharmacology , Neuralgia/drug therapy , Opioid Peptides/pharmacology , Receptors, Opioid/agonists , Spiro Compounds/pharmacology , Analgesics/pharmacology , Animals , Chronic Pain/drug therapy , Chronic Pain/metabolism , Disease Models, Animal , Male , Mice , Morphine/pharmacology , Neuralgia/metabolism , Pain Measurement/methods , Simvastatin/pharmacology , NociceptinABSTRACT
Synthesis and investigation of antifungal, anticonvulsant and anti-Toxoplasma gondii activities of ten novel (2-(cyclopropylmethylidene)hydrazinyl)thiazole 3a-3j are presented. Among the derivatives, compounds 3a-3d and 3f-3j possess very high activity against Candida spp. ATCC with MIC = 0.015-7.81 µg/ml. Compounds 3a-3d and 3f-3j possess also very high activity towards most of strains of Candida spp. isolated from clinical materials with MIC = 0.015-7.81 µg/ml. The activity of these compounds is similar and even higher than the activity of nystatin used as positive control. Additionally, compounds 3c and 3e showed interesting anticonvulsant activities in the MES test, whereas compounds 3f and 3i demonstrated the anticonvulsant activity in PTZ-induced seizures. Noteworthy, none of these compounds impaired animals' motor skills in the rotarod test. Moreover, thiazoles 3a, 3h, and 3j showed significant anti-Toxoplasma gondii activity, with IC50 values 31-52 times lower than those observed for sulfadiazine. The results of the cytotoxicity evaluation, anti-Candida spp. and anti-Toxoplasma gondii activity studies showed that Candida spp. and Toxoplasma gondii growth was inhibited at non-cytotoxic concentrations for the mouse L929 fibroblast and the African green monkey kidney (VERO) cells. Molecular docking studies indicated secreted aspartic proteinase (SAP) as possible antifungal target.
ABSTRACT
OBJECTIVES: Cognitive deficits are one of the frequent symptoms accompanying epilepsy or its treatment. METHODS: In this study, the effect on cognition of intraperitoneally administered antiepileptic drug, pregabalin (10 mg/kg), was investigated in scopolamine-induced memory-impaired mice in the passive avoidance task and Morris water maze task. The effect of scopolamine and pregabalin on animals' locomotor activity was also studied. RESULTS: In the retention phase of the passive avoidance task, pregabalin reversed memory deficits induced by scopolamine (p < 0.05). During the acquisition phase of the Morris water maze pregabalin-treated memory-impaired mice performed the test with longer escape latencies than the vehicle-treated mice (significant at p < 0.05 on Day 5, and at p < 0.001 on Day 6). There were no differences in this parameter between the scopolamine-treated control group and pregabalin-treated memory-impaired mice, which indicated that pregabalin had no influence on spatial learning in this task. During the probe trial a significant difference (p < 0.05) was observed in terms of the mean number of target crossings between vehicle-treated mice and pregabalin-treated memory-impaired mice but there was no difference between the scopolamine-treated control group and mice treated with pregabalin + scopolamine. Pregabalin did not influence locomotor activity increased by scopolamine. DISCUSSION: In passive avoidance task, pregabalin reversed learning deficits induced by scopolamine. In the Morris water maze, pregabalin did not influence spatial learning deficits induced by scopolamine. These results are relevant for epileptic patients treated with pregabalin and those who use it for other therapeutic indications (anxiety, pain).
Subject(s)
Amnesia/drug therapy , Anticonvulsants/therapeutic use , Avoidance Learning/drug effects , Fear , Pregabalin/therapeutic use , Spatial Learning/drug effects , Amnesia/chemically induced , Amnesia/psychology , Animals , Conditioning, Psychological , Disease Models, Animal , Fear/psychology , Male , Maze Learning/drug effects , Mice , Mice, Inbred C57BL , Scopolamine , Species SpecificityABSTRACT
This paper describes the synthesis of the library of 22 new 3-methyl- and 3-ethyl-3-methyl-2,5-dioxo-pyrrolidin-1-yl-acetamides as potential anticonvulsant agents. The maximal electroshock (MES) and the subcutaneous pentylenetetrazole (scPTZ) seizure models were used for screening all the compounds. The 6 Hz model of pharmacoresistant limbic seizures was applied for studying selected derivatives. Six amides were chosen for pharmacological characterization of their antinociceptive activity in the formalin model of tonic pain as well as local anesthetic activity was assessed in mice. The pharmacological data indicate on the broad spectra of activity across the preclinical seizure models. Compounds 10 (ED50=32.08 mg/kg, MES test) and 9 (ED50=40.34 mg/kg, scPTZ test) demonstrated the highest potency. These compounds displayed considerably better safety profiles than clinically relevant antiepileptic drugs phenytoin, ethosuximide, or valproic acid. Several molecules showed antinociceptive and local anesthetic properties. The in vitro radioligand binding studies demonstrated that the influence on the sodium and calcium channels may be one of the essential mechanisms of action.
Subject(s)
Amides/pharmacology , Anticonvulsants/chemical synthesis , Anticonvulsants/pharmacology , Pyrrolidines/pharmacology , Seizures/drug therapy , Amides/administration & dosage , Amides/chemical synthesis , Amides/chemistry , Animals , Anticonvulsants/administration & dosage , Anticonvulsants/chemistry , Disease Models, Animal , Dose-Response Relationship, Drug , Electroshock , Injections, Intraperitoneal , Injections, Subcutaneous , Male , Mice , Molecular Structure , Pentylenetetrazole/administration & dosage , Pyrrolidines/administration & dosage , Pyrrolidines/chemistry , Seizures/chemically inducedABSTRACT
Synthesis, characterization and investigation of in vivo anticonvulsant activities of 13 novel cyclopentanecarbaldehyde-based 2,4-disubstituted 1,3-thiazoles are presented. Their structures were determined using (1)H and (13)C NMR, FAB(+)-MS, HRMS and elemental analyses. The results of anticonvulsant screening reveal that seven intraperitoneally administered compounds: 3a, 3b, 3d, 3e, 3f, 3k and 3m containing F-, Cl-, Br-, CF3-, CH3- and adamantyl substituents demonstrated significant anticonvulsant activity in the pentylenetetrazole model with median effective doses (ED50) ≤ 20 mg/kg, respectively, which was approximately seven-fold lower than that reported for the reference drug, ethosuximide. Noteworthy, none of these compounds impaired animals' motor skills in the rotarod test.
Subject(s)
Anticonvulsants/chemical synthesis , Anticonvulsants/pharmacology , Disease Models, Animal , Seizures/prevention & control , Thiazoles/chemical synthesis , Thiazoles/pharmacology , Animals , Carbon-13 Magnetic Resonance Spectroscopy , Male , Mass Spectrometry/methods , Mice , Pilocarpine/administration & dosage , Proton Magnetic Resonance Spectroscopy , Rotarod Performance TestABSTRACT
Synthesis and investigation of antimicrobial activity of 22 novel thiazoles and selenazoles derived from dihydro-2H-thiopyran-4(3H)-one are presented. Additionally, anticonvulsant activity of six derivatives is examinated. Among the derivatives, compounds 4a-f, 4i, 4k, 4 l, 4n, 4o-s and 4v have very strong activity against Candida spp. with MIC = 1.95-15.62 µg/ml. In the case of compounds 4a-f, 4i, 4k, 4 l, 4n, 4o, 4r and 4s, the activity is very strong against some strains of Candida spp. isolated from clinical materials, with MIC = 0.98 to 15.62 µg/ml. Additionally, compounds 4n-v are found to be active against Gram-positive bacteria with MIC = 7.81-62.5 µg/ml. The results of anticonvulsant screening reveal that compounds 4a, 4b, 4m and 4n demonstrate a statistically significant anticonvulsant activity in the pentylenetetrazole model, whereas compounds 4a and 4n showed protection in 6-Hz psychomotor seizure model. Noteworthy, none of these compounds impaired animals' motor skills in the rotarod test. We also performed quantum chemical calculation of interaction and binding energies in complex of 4a with cyclodextrin.