ABSTRACT
Antiseizure drugs (ASDs) are commonly used to treat a wide range of nonepileptic conditions, including pain. In this context, the analgesic effect of four pyrrolidine-2,5-dione derivatives (compounds 3, 4, 6, and 9), with previously confirmed anticonvulsant and preliminary antinociceptive activity, was assessed in established pain models. Consequently, antinociceptive activity was examined in a mouse model of tonic pain (the formalin test). In turn, antiallodynic and antihyperalgesic activity were examined in the oxaliplatin-induced model of peripheral neuropathy as well as in the streptozotocin-induced model of painful diabetic neuropathy in mice. In order to assess potential sedative properties (drug safety evaluation), the influence on locomotor activity was also investigated. As a result, three compounds, namely 3, 6, and 9, demonstrated a significant antinociceptive effect in the formalin-induced model of tonic pain. Furthermore, these substances also revealed antiallodynic properties in the model of oxaliplatin-induced peripheral neuropathy, while compound 3 attenuated tactile allodynia in the model of diabetic streptozotocin-induced peripheral neuropathy. Apart from favorable analgesic properties, the most active compound 3 did not induce any sedative effects at the active dose of 30 mg/kg after intraperitoneal (i.p.) injection.
Subject(s)
Diabetic Neuropathies , Neuralgia , Analgesics/pharmacology , Analgesics/therapeutic use , Animals , Diabetic Neuropathies/drug therapy , Disease Models, Animal , Hyperalgesia/drug therapy , Mice , Neuralgia/drug therapy , Oxaliplatin/therapeutic use , Pyrrolidines , StreptozocinABSTRACT
The aim of this study was to design and synthesize two new series of pyrrolidine-2,5-dione-acetamides with a benzhydryl or sec-butyl group at position 3 as potential anticonvulsants. Their anticonvulsant activity was evaluated in standard animal models of epilepsy: the maximal electroshock (MES), the 6â Hz, and the subcutaneous pentylenetetrazole (scPTZ) tests. The inâ vivo studies revealed the most potent anticonvulsant activity for 15 (3-(sec-butyl)-1-(2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)-2-oxoethyl)pyrrolidine-2,5-dione), with ED50 values of 80.38â mg/kg (MES) and 108.80â mg/kg (6â Hz). The plausible mechanism of action was assessed in inâ vitro binding assays, in which 15 interacted effectively with voltage-gated sodium (site 2) and L-type calcium channels at a concentration of 100â µM. Subsequently, the antinociceptive activity of compounds 7 and 15 was observed in the hot plate test of acute pain. Moreover, compounds 7, 11 and 15 demonstrated an analgesic effect in the formalin test of tonic pain. The hepatotoxic properties of the most effective compounds (7, 11 and 15) in HepG2 cells were also investigated.
Subject(s)
Acetic Acid/pharmacology , Amides/pharmacology , Analgesics/pharmacology , Antineoplastic Agents/pharmacology , Pain/drug therapy , Seizures/drug therapy , Acetic Acid/chemical synthesis , Acetic Acid/chemistry , Amides/chemical synthesis , Amides/chemistry , Analgesics/chemical synthesis , Analgesics/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Design , Drug Screening Assays, Antitumor , Formaldehyde , Hep G2 Cells , Humans , Molecular Structure , Pain/chemically induced , Seizures/chemically induced , Structure-Activity RelationshipABSTRACT
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
The present study aimed to design and synthesize a new series of hybrid compounds with pyrrolidine-2,5-dione and thiophene rings in the structure as potential anticonvulsant and antinociceptive agents. For this purpose, we obtained a series of new compounds and evaluated their anticonvulsant activity in animal models of epilepsy (maximal electroshock (MES), psychomotor (6 Hz), and subcutaneous pentylenetetrazole (scPTZ) seizure tests). To determine the mechanism of action of the most active anticonvulsant compounds (3, 4, 6, 9), their influence on the voltage-gated sodium and calcium channels as well as GABA transporter (GAT) was assessed. The most promising compound 3-(3-methylthiophen-2-yl)-1-(3-morpholinopropyl)pyrrolidine-2,5-dione hydrochloride (4) showed higher ED50 value than those of the reference drugs: valproic acid (VPA) and ethosuximide (ETX) (62.14 mg/kg vs. 252.7 mg/kg (VPA) in the MES test, and 75.59 mg/kg vs. 130.6 mg/kg (VPA) and 221.7 mg/kg (ETX) in the 6 Hz test, respectively). Moreover, in vitro studies of compound 4 showed moderate but balanced inhibition of the neuronal voltage-sensitive sodium (site 2) and L-type calcium channels. Additionally, the antinociceptive activity of the most active compounds (3, 4, 6, 9) was also evaluated in the hot plate test and writhing tests, and their hepatotoxic properties in HepG2 cells were also investigated. To determine the possible mechanism of the analgesic effect of compounds 3, 6, and 9, the affinity for the TRPV1 receptor was investigated.
Subject(s)
Analgesics/chemical synthesis , Analgesics/pharmacology , Anticonvulsants/chemical synthesis , Anticonvulsants/pharmacology , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacology , Analgesics/chemistry , Animals , Anticonvulsants/chemistry , Cell Survival/drug effects , Hep G2 Cells , Humans , Male , Mice , Pyrrolidines/chemistryABSTRACT
The objective of this study was to evaluate analgesic and antiallodynic activity of four new 3-benzhydryl-pyrrolidine-2,5-dione derivatives, which demonstrated previously anticonvulsant activity in the seizure tests in mice. Analgesic activity was examined in acute (the hot plate test), tonic (the formalin test), as well as neuropathic (the oxaliplatin-induced peripheral neuropathy) pain models in mice. Moreover, potential sedative properties and hepatotoxicity were evaluated. To establish the plausible mechanism of action, in vitro assays were carried out. All tested compounds RS 34, RS 37, RS 48, and RS 49, similarly to pregabalin, were active in the second phase of formalin test, a model of tonic pain. The most promising effect was observed for compounds RS 34, RS 48, and RS 49, which in a statistically significant way attenuated the nocifensive response at all tested doses 1, 10, and 30 mg/kg. Furthermore, all compounds at a dose of 30 mg/kg revealed antiallodynic activity in neuropathic pain related to chemotherapy-induced peripheral neuropathy in mice. In experimental tests on three compounds RS 34, RS 37 and RS 48 at active doses no sedative properties were registered. In the in vitro assay the selected molecule RS 34 did not induce cytotoxic effect on hepatoma cells. The binding and functional studies did not provide firm evidence on possible mechanism of action of these derivatives. In conclusion, the tested pyrrolidine-2,5-dione derivatives with antiseizure activity exerted also analgesic and antiallodynic effects in mouse models of pain.
Subject(s)
Acute Pain/drug therapy , Analgesics/therapeutic use , Anticonvulsants/therapeutic use , Hyperalgesia/drug therapy , Neuralgia/drug therapy , Pyrrolidines/therapeutic use , Analgesics/pharmacology , Animals , Anticonvulsants/pharmacology , Disease Models, Animal , Formaldehyde , Hep G2 Cells , Hot Temperature , Humans , Locomotion/drug effects , Male , Mice , Oxaliplatin , Pyrrolidines/pharmacologyABSTRACT
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
Anticonvulsant drugs are used to treat a wide range of non-epileptic conditions, including chronic pain. The aim of the present experiments was to examine analgesic activity of three new 3,3-diphenyl-propionamides, which had previously demonstrated anticonvulsant activity in the MES (maximal electroshock seizure), scPTZ (subcutaneous pentylenetetrazole) and/or 6Hz (psychomotor seizure) tests in mice. Antinociceptive activity was examined in mouse models of acute pain (the hot plate test) and tonic pain (the formalin test) in mice. Antiallodynic and antihyperalgesic activity was estimated in the oxaliplatin-induced neuropathic pain model of chemotherapy-induced peripheral neuropathy and in the streptozotocin-induced model of painful diabetic neuropathy in mice. Considering the drug safety evaluation, the influence on locomotor activity was checked. Moreover, using in vitro methods, selected compound was tested for potential hepatotoxicity on human hepatocellular carcinoma cell line and for metabolic stability. To determine the plausible mechanism of anticonvulsant and antinociceptive action, in vitro binding and functional assays were carried out. Among tested molecules two of them JOA 122 (3p) and JOA 123 (3q) revealed significant antinociceptive activity in the model of tonic pain - the formalin test and neuropathic pain models - the oxaliplatin and streptozotocin-induced peripheral neuropathy. In the binding studies JOA 122 (3p) revealed the high affinity to voltage-gated sodium channels (Nav1.2), as well as for 5-HT1A receptors. Metabolism studies in mouse liver microsomes showed a low metabolic stability of this compound.
Subject(s)
Amides/pharmacology , Analgesics/pharmacology , Anticonvulsants/pharmacology , Pain Measurement/drug effects , Piperazines/pharmacology , Amides/pharmacokinetics , Analgesics/pharmacokinetics , Animals , Anticonvulsants/pharmacokinetics , Cell Line, Tumor , Disease Models, Animal , Dose-Response Relationship, Drug , Humans , Locomotion/drug effects , Mice , Microsomes, Liver/metabolism , Piperazines/pharmacokinetics , Radioligand Assay , Serotonin 5-HT1 Receptor Antagonists/pharmacology , Voltage-Gated Sodium Channel Blockers/pharmacologyABSTRACT
A new series of 1,3-substituted pyrrolidine-2,5-dione derivatives as potential anticonvulsant agents are described. Initial pharmacological screening of these compounds was performed by using acute models of seizures (MES and scPTZ tests) in mice after intraperitoneal administration. Quantitative pharmacological research revealed that the most promising compounds were N-[{4-(3-trifluoromethylphenyl)piperazin-1-yl}propyl]-3-benzhydrylpyrrolidine-2,5-dione monohydrochloride (11) with a ED50 value of 75.9â mg kg-1 (MES test) and N-[{4-(3,4-dichlorophenyl)piperazin-1-yl}ethyl]-3-methylpyrrolidine-2,5-dione monohydrochloride (18) with ED50 =88.2â mg kg-1 (MES test) and ED50 =65.7â kg mg-1 (scPTZ test). These compounds displayed a more beneficial protective index than well-known antiepileptic drugs. A plausible mechanism of action of compounds 11 and 18 [molecule 11 blocked the sodium channel (siteâ 2) and 18 blocked both the sodium (siteâ 2) and L-type calcium channels] and their preliminary safety inâ vitro were evaluated. Besides, the lipophilicity of all synthesized compounds was determined by using UPLC-MS.
Subject(s)
Anticonvulsants/pharmacology , Piperazines/pharmacology , Pyrrolidines/pharmacology , Seizures/drug therapy , Animals , Anticonvulsants/administration & dosage , Anticonvulsants/chemistry , Calcium Channels, L-Type/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Disease Models, Animal , Humans , Hydrophobic and Hydrophilic Interactions , Injections, Intraperitoneal , Mice , Molecular Structure , Piperazine , Piperazines/administration & dosage , Piperazines/chemistry , Pyrrolidines/administration & dosage , Pyrrolidines/chemistry , Structure-Activity Relationship , Voltage-Gated Sodium Channels/metabolismABSTRACT
The focused library of new amides derived from 3,3-diphenyl-2,5-dioxo-pyrrolidin-1-yl-acetic acid (2a-t) and 3,3-diphenyl-propionic acid (3a-t) as potential anticonvulsant agents was synthesized. The final products were obtained in the amidation reaction of the given carboxylic acid (2, 3) with appropriate secondary amines in the presence of carbonyldiimidazole (CDI) as a coupling reagent. The initial anticonvulsant screening was performed in mice intraperitoneally (i.p.) using the "classical" maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure models, whereas the acute neurological toxicity was determined applying the rotarod test. Additionally, several compounds were studied also in the 6-Hz seizures recognized as the animal model of human pharmacoresistant epilepsy. In this series, compound 3q displayed a broad spectrum of activity across the preclinical seizure models (ED50 MES = 31.64 mg/kg; ED50 scPTZ = 75.41 mg/kg, ED50 6-Hz (32 mA) = 38.15 mg/kg). Consequently, compound 3q revealed a wider spectrum of protection, higher activity or/and a better safety profile than the commonly used antiepileptic drugs such as phenytoin, ethosuximide, valproic acid, or/and levetiracetam. Notably, the in vitro studies showed that the most possible mechanism of action of 3q may be connected to the interaction with neuronal voltage-sensitive sodium channels (site 2). Other substances were active predominantly in the chemically induced seizures. The results of the current studies indicate that the presence of the pyrrolidine-2,5-dione ring is important but not indispensable for anticonvulsant activity.
Subject(s)
Acetamides/pharmacology , Amides/pharmacology , Anticonvulsants/pharmacology , Piperazines/pharmacology , Seizures/drug therapy , Acetamides/chemical synthesis , Acetamides/chemistry , Amides/chemical synthesis , Amides/chemistry , Animals , Anticonvulsants/chemical synthesis , Anticonvulsants/chemistry , Dose-Response Relationship, Drug , Electroshock , Male , Mice , Molecular Structure , Piperazines/chemical synthesis , Piperazines/chemistryABSTRACT
The aim of this paper was to describe the synthesis of a library of 28 new 1,3-substituted pyrrolidine-2,5-dione as potential anticonvulsant agents. The anticonvulsant activity was evaluated using three acute models of seizures in mice (MES-maximal electroshock, scPTZ-subcutaneous pentylenetetrazole, and 6Hz-psychomotor seizure tests). The neurotoxicity was determined by rotarod test. The most promising compound was found to be N-[{morpholin-1-yl}-methyl]-3-benzhydryl-pyrrolidine-2,5-dione (15), as it was active in the MES (ED50=41.0mg/kg), scPTZ (ED50=101.6kg/mg), and 6Hz (ED50=45.42mg/kg) tests. This compound displayed more beneficial protection index (PI) than antiepileptic drugs such as ethosuximide, lacosamide and valproic acid. In vitro studies for compound 15 were conducted and provided information that its possible mechanism of action is related to blocking of the neuronal voltage-sensitive sodium (site 2) and L-type calcium channels.
Subject(s)
Anticonvulsants/chemical synthesis , Anticonvulsants/therapeutic use , Mannich Bases/chemistry , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacology , Seizures/drug therapy , Animals , Mice , Pyrrolidines/therapeutic useABSTRACT
The purpose of the present study was to examine the analgesic activity of six novel hybrid molecules, which demonstrated in the previous research anticonvulsant activity in the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole seizure (scPTZ) tests in mice. The antinociceptive properties were estimated in three models of pain in mice-the hot plate test, the formalin test, and in the oxaliplatin-induced neuropathy. Moreover, extended anticonvulsant studies were carried out and the antiseizure activity was investigated in the 6-Hz test. Considering drug safety evaluation, the influence of compounds on locomotor activity and contextual memory were checked. Furthermore, chosen molecules were tested in vitro for potential hepatotoxicity. To explain the probable mechanism of action, the radioligand binding assays were performed. In both phases of formalin test, analgesic activity demonstrated compounds 4, 8, and 9. These agents relieved also mechanical allodynia in oxaliplatin-induced model of neuropathic pain. At active doses, they did not influence locomotor activity of mice. Moreover, for compounds 8 and 9, no deleterious effect on memory was observed, but compound 4 might induce memory deficits. All tested compounds (4, 5, 8, 9, 15, and 16) inhibited psychomotor seizures with the ED50 values = 24.66-47.21 mg/kg. The binding studies showed that compound 4 only at the high concentrations revealed the effective binding to the neuronal sodium channels and moderately binding to the L-type calcium (verapamil site) channels and NMDA receptors. The present preclinical results proved that novel hybrid molecules demonstrate very promising anticonvulsant and analgesic activity.
Subject(s)
Amides/pharmacology , Analgesics/pharmacology , Anticonvulsants/pharmacology , Pain/drug therapy , Amides/chemical synthesis , Amides/chemistry , Analgesics/chemical synthesis , Analgesics/chemistry , Animals , Anticonvulsants/chemical synthesis , Anticonvulsants/chemistry , Disease Models, Animal , Epilepsy/drug therapy , Epilepsy/physiopathology , Male , Mice , Motor Activity/drug effects , Neuralgia/drug therapy , Neuralgia/pathology , Pain/pathology , Pain Measurement , Pentylenetetrazole/administration & dosage , Seizures/drug therapy , Seizures/physiopathology , Structure-Activity RelationshipABSTRACT
The focused library of 21 new N-phenyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide, 2-(3-methyl-2,5-dioxopyrrolidin-1-yl)propanamide, and 2-(2,5-dioxopyrrolidin-1-yl)butanamide derivatives as potential new hybrid anticonvulsant agents was synthesized. These hybrid molecules were obtained as close analogs of previously described N-benzyl derivatives and fuse the chemical fragments of clinically relevant antiepileptic drugs such as ethosuximide, levetiracetam, and lacosamide. The initial anticonvulsant screening was performed in mice (ip) using the 'classical' maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests, as well as in the six-Hertz (6Hz) model of pharmacoresistant limbic seizures. Applying the rotarod test, the acute neurological toxicity was determined. The broad spectra of activity across the preclinical seizure models in mice (ip) displayed compounds 4, 5, 11, and 19. The most favorable anticonvulsant properties demonstrated 4 (ED50 MES=96.9mg/kg, ED50scPTZ=75.4mg/kg, ED50 6Hz=44.3mg/kg) which showed TD50=335.8mg/kg in the rotarod test that yielded satisfying protective indexes (PI MES=3.5, PI scPTZ=4.4, PI 6Hz=7.6). Consequently, compound 4 revealed comparable or better safety profile than model antiepileptic drugs (AEDs): ethosuximide, lacosamide, and valproic acid. In the in vitro assays, compound 4 was observed as relatively effective binder to the neuronal voltage-sensitive sodium and diltiazem site of L-type calcium channels.
Subject(s)
Amides/chemical synthesis , Amides/therapeutic use , Anticonvulsants/chemical synthesis , Anticonvulsants/therapeutic use , Drug Design , Seizures/drug therapy , Amides/chemistry , Amides/pharmacology , Animals , Anticonvulsants/administration & dosage , Anticonvulsants/pharmacology , Calcium Channels/drug effects , Humans , Injections, Intraperitoneal , Mice , Molecular Structure , Neurons/drug effects , Pyrrolidines/chemical synthesis , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Pyrrolidines/therapeutic useABSTRACT
Two series of new derivatives of pyrrolidine-2,5-dione were synthesized and evaluated for their anticonvulsant properties. Initial screening for their anticonvulsant properties was performed in mice after intraperitoneal administration, using the maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) and 6-Hz seizure tests. Quantitative pharmacological research revealed that the highest level of protection was demonstrated by compound N-[{4-methylpiperazin-1-yl}-methyl]-3-(1-phenylethyl)-pyrrolidine-2,5-dione monohydrochloride (22) which was effective both in the scPTZ test (ED50=39 mg/kg) and in the 6-Hz test (ED50=36 mg/kg). This molecule showed higher potency than reference antiepileptic drugs such as ethosuximide, lacosamide and valproic acid. With the aim of explaining the possible mechanism of action of the selected molecule, its influence on sodium and calcium channels as well as NMDA and GABAA receptors binding properties were evaluated in vitro.
Subject(s)
Anticonvulsants/pharmacology , Mannich Bases/pharmacology , Piperazines/pharmacology , Pyrrolidines/pharmacology , Succinimides/pharmacology , Animals , Anticonvulsants/chemical synthesis , Anticonvulsants/chemistry , Calcium Channel Blockers/chemical synthesis , Calcium Channel Blockers/chemistry , Calcium Channel Blockers/pharmacology , Calcium Channels, L-Type/metabolism , GABA-A Receptor Antagonists/chemical synthesis , GABA-A Receptor Antagonists/chemistry , GABA-A Receptor Antagonists/pharmacology , Mannich Bases/chemical synthesis , Mannich Bases/chemistry , Mice , Piperazines/chemical synthesis , Pyrrolidines/chemical synthesis , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Sodium Channel Blockers/chemical synthesis , Sodium Channel Blockers/chemistry , Sodium Channel Blockers/pharmacology , Structure-Activity Relationship , Succinimides/chemical synthesis , Succinimides/chemistryABSTRACT
The aim of the present experiments was to examine the anticonvulsant and antinociceptive activity of five new amides derived from 3-phenyl-2,5-dioxo-pyrrolidine-1-yl-acetic acid in animal models of seizures and pain. The antiseizure activity was investigated in three acute models of seizures, namely, the maximal electroshock (MES), the subcutaneous pentylenetetrazole (scPTZ), and 6Hz psychomotor seizure tests in mice. The antinociceptive properties were estimated in the formalin model of tonic pain, and in the oxaliplatin-induced neuropathic pain model in mice. Considering drug safety evaluation, acute neurological toxicity was determined in the rotarod test. Three tested compounds (3, 4, and 7) displayed a broad spectrum of anticonvulsant activity and showed better protective indices than those obtained for MES/scPTZ/6Hz active reference drug - valproic acid. Furthermore, three compounds (3, 4, and 6) demonstrated a significant antinociceptive effect in the formalin test, as well as antiallodynic activity in the oxaliplatin-induced neuropathic pain model. Among the tested agents, compounds 3 and 4 displayed not only antiseizure properties, but also collateral prominent analgesic properties. The in vitro binding study indicated that the plausible mechanism of action of chosen compound (4) was the influence on neuronal voltage-sensitive sodium (site 2) and L-type calcium channels.
Subject(s)
Acetic Acid/chemistry , Acetic Acid/pharmacology , Amides/chemistry , Analgesics/chemistry , Analgesics/pharmacology , Anticonvulsants/chemistry , Anticonvulsants/pharmacology , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Acetic Acid/metabolism , Acetic Acid/therapeutic use , Analgesics/metabolism , Analgesics/therapeutic use , Animals , Anticonvulsants/metabolism , Anticonvulsants/therapeutic use , Binding Sites , Calcium Channels/metabolism , Male , Mice , Neuralgia/drug therapy , Neuralgia/metabolism , Pyrrolidines/metabolism , Pyrrolidines/therapeutic use , Sodium Channels/metabolismABSTRACT
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
The purpose of this study was to synthetize the focused library of 34 new piperazinamides of 3-methyl- and 3,3-dimethyl-(2,5-dioxopyrrolidin-1-yl)propanoic or butanoic acids as potential new hybrid anticonvulsants. These hybrid molecules join the chemical fragments of well-known antiepileptic drugs (AEDs) such as ethosuximide, levetiracetam, and lacosamide. Compounds 5-38 were prepared in a coupling reaction of the 3-methyl- or 3,3-dimethyl-2-(2,5-dioxopyrrolidin-1-yl)propanoic (1, 2) or butanoic acids (3, 4) with the appropriately substituted secondary amines in the presence of the N,N-carbonyldiimidazole reagent. The initial anticonvulsant screening was performed in mice (ip) using the 'classical' maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests as well as in the six-Hertz (6Hz) model of pharmacoresistant limbic seizures. The acute neurological toxicity was determined applying the chimney test. The broad spectra of activity across the preclinical seizure models in mice ip displayed compounds 7, 15, and 36. The most favorable anticonvulsant properties demonstrated 15 (ED50 MES=74.8mg/kg, ED50scPTZ=51.6mg/kg, ED50 6Hz=16.8mg/kg) which showed TD50=213.3mg/kg in the chimney test that yielded satisfying protective indexes (PI MES=2.85, PI scPTZ=4.13, PI 6Hz=12.70) at time point of 0.5h. As a result, compound 15 displayed comparable or better safety profile than clinically relevant AEDs: ethosuximide, lacosamide or valproic acid. In the in vitro assays compound 15 was observed as relatively effective binder to the neuronal voltage-sensitive sodium and L-type calcium channels. Beyond the anticonvulsant properties, 6 compounds diminished the pain responses in the formalin model of tonic pain in mice.
Subject(s)
Analgesics/pharmacology , Anticonvulsants/pharmacology , Pain/drug therapy , Piperazines/pharmacology , Pyrrolidinones/pharmacology , Seizures/drug therapy , Analgesics/administration & dosage , Analgesics/chemistry , Animals , Anticonvulsants/administration & dosage , Anticonvulsants/chemistry , Disease Models, Animal , Dose-Response Relationship, Drug , Electroshock , Injections, Intraperitoneal , Mice , Molecular Structure , Pain Measurement , Pentylenetetrazole/administration & dosage , Piperazines/chemical synthesis , Piperazines/chemistry , Pyrrolidinones/chemical synthesis , Pyrrolidinones/chemistry , Seizures/chemically inducedABSTRACT
Synthesis and anticonvulsant properties of 26 new N-Mannich bases of 3-benzhydryl-(5-17) and 3-isopropyl-pyrrolidine-2,5-diones (18-30) have been described. Initial anticonvulsant screening for these compounds was evaluated in mice after intraperitoneal administration in the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizures tests. The acute neurological toxicity was determined by applying the rotorod test. The in vivo results in mice showed that the majority of 3-benzhydryl-pyrrolidine-2,5-dione derivatives revealed effectiveness, while 3-isopropyl-pyrrolidine-2,5-dione derivatives were practically devoid of activity. The quantitative evaluation in both tests revealed that the most active were N-[{4-(3-chlorophenyl)-piperazin-1-yl}-methyl]-3-benzhydryl-pyrrolidine-2,5-dione (9) with ED5 0 value =42.71 mg/kg (MES), ED5 0 value >150 mg/kg (scPTZ), and N-[{4-(3-trifluoromethylphenyl)-piperazin-1-yl}-methyl]-3-benzhydryl-pyrrolidine-2,5-dione (13) with ED5 0 value =101.46 mg/kg (MES) and ED5 0 value =72.59 mg/kg (scPTZ). These molecules showed higher potency and lower neurotoxicity than the reference antiepileptic drugs (ethosuximide and valproic acid). To explain the probable mechanism of action of selected active derivatives (9 and 13), their influence on Nav1.2 and l-type calcium channel was evaluated in vitro.
Subject(s)
Anticonvulsants/pharmacology , Mannich Bases/chemistry , Pyrrolidines/pharmacology , Anticonvulsants/chemical synthesis , Proton Magnetic Resonance Spectroscopy , Pyrrolidines/chemical synthesis , Pyrrolidines/chemistry , Spectrometry, Mass, Electrospray IonizationABSTRACT
The aim of the present experiments was to examine anticonvulsant activity of new pyrrolidine-2,5-dione and 3-methylpyrrolidine-2,5-dione derivatives in animal models of epilepsy. In addition, the possible collateral antinociceptive activity was assessed. Anticonvulsant activity was investigated in the electroconvulsive threshold (MEST) test and the pilocarpine-induced seizure models in mice. Antinociceptive activity was examined in the hot plate and the formalin tests in mice. Considering the drug safety evaluation, the Vibrio harveyi test was used to estimate anti/mutagenic activity. To determine the plausible mechanism of anticonvulsant action, for two chosen compounds (12 and 23), in vitro binding assays were carried out. All of the tested compounds revealed significant anticonvulsant activity in the MEST test. Compounds 12 and 23 displayed anticonvulsant effect also in pilocarpine-induced seizures. Four of the tested compounds (12, 13, 15, and 24) revealed analgesic activity in the hot plate test as well as in the first phase of the formalin test, and all of them were active in the second phase of the formalin test. The possible mechanism of action of compounds 12 and 23 is the influence on the neuronal voltage-sensitive sodium and L-type calcium channels. The obtained results indicate that in the group of pyrrolidine-2,5-diones, new anticonvulsants with collateral analgesic properties can be found.
Subject(s)
Analgesics/therapeutic use , Anticonvulsants/therapeutic use , Mannich Bases/therapeutic use , Pain/drug therapy , Seizures/drug therapy , Succinimides/therapeutic use , Analgesics/pharmacology , Animals , Anticonvulsants/pharmacology , Calcium Channels, L-Type/metabolism , Formaldehyde , Hot Temperature , Male , Mannich Bases/pharmacology , Mice , Motor Activity/drug effects , Mutagenicity Tests , Pain/etiology , Pilocarpine , Seizures/chemically induced , Sodium Channels/metabolism , Succinimides/pharmacology , Vibrio/drug effects , Vibrio/geneticsABSTRACT
A series of new 3-methyl-3-phenyl-2,5-dioxo-pyrrolidin-1-yl-acetamides (6-23) has been synthesized and evaluated for their anticonvulsant activity in the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests after intraperitoneal injection in mice. The acute neurological toxicity was determined using the rotarod test. The in vivo preliminary pharmacological results showed that in the whole series only two compounds (15, 21) were devoid of activity, whereas other molecules revealed protection in at least one animal model of epilepsy (MES or/and scPTZ). The in vivo quantitative studies in mice showed that in the MES test the most active were 1-{2-[4-(2-methoxyphenyl)-piperazin-1-yl]-2-oxo-ethyl}-3-methyl-3-phenyl-pyrrolidine-2,5-dione (17), 1-{2-[4-(4-fluorophenyl)-piperazin-1-yl]-2-oxo-ethyl}-3-methyl-3-phenyl-pyrrolidine-2,5-dione (8), and its 2-fluorophenyl analog (7) with ED50 values of 97.51 mg/kg (17), 104.11 mg/kg (8), and 114.68 mg/kg (7), respectively. In the scPTZ screen the most potent were compound 6 with an ED50 = 40.87 mg/kg, and 4-benzylpiperidine derivative 22 - ED50 = 60.00 mg/kg. Furthermore, selected compounds 8, 14, 17, and 23 were tested in the psychomotor seizure 6-Hz test. Compounds 7, 8, and 17 revealed significant analgesic activity in the formalin model of tonic pain in mice, without impairment of the motor coordination in the chimney test. The in vitro binding studies showed that the mechanism of anticonvulsant activity may be partially related with the influence on the voltage-gated sodium and calcium channels. The mutagenic and antimutagenic effects of 13, 17, and 22 were evaluated using the novel Vibrio harveyi assay.
Subject(s)
Acetates/pharmacology , Amides/pharmacology , Anticonvulsants/pharmacology , Drug Design , Pyrrolidines/pharmacology , Seizures/drug therapy , Acetates/chemistry , Amides/administration & dosage , Amides/chemistry , Animals , Anticonvulsants/administration & dosage , Anticonvulsants/chemistry , Disease Models, Animal , Dose-Response Relationship, Drug , Electroshock , Injections, Intraperitoneal , Mice , Molecular Structure , Pyrrolidines/chemistryABSTRACT
Twenty-two new N-phenyl-2-(4-phenylpiperazin-1-yl)acetamide derivatives have been synthesized and evaluated for their anticonvulsant activity in animal models of epilepsy. These molecules have been designed as analogs of previously obtained anticonvulsant active pyrrolidine-2,5-diones in which heterocyclic imide ring has been changed into chain amide bound. The final compounds were synthesized in the alkylation reaction of the corresponding amines with the previously obtained alkylating reagents 2-chloro-1-(3-chlorophenyl)ethanone (1) or 2-chloro-1-[3-(trifluoromethyl)phenyl]ethanone (2). Initial anticonvulsant screening was performed using standard maximal electroshock (MES) and subcutaneous pentylenetetrazole screens in mice and/or rats. Several compounds were tested additionally in the psychomotor seizures (6-Hz model). The acute neurological toxicity was determined applying the rotarod test. The results of pharmacological studies showed activity exclusively in the MES seizures especially for 3-(trifluoromethyl)anilide derivatives, whereas majority of 3-chloroanilide analogs were inactive. It should be emphasize that several molecules showed also activity in the 6-Hz screen which is an animal model of human partial and therapy-resistant epilepsy. In the in vitro studies, the most potent derivative 20 was observed as moderate binder to the neuronal voltage-sensitive sodium channels (site 2). The SAR studies for anticonvulsant activity confirmed the crucial role of pyrrolidine-2,5-dione core fragment for anticonvulsant activity.