RESUMEN
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.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Imidazolidinas/uso terapéutico , Bases de Mannich/uso terapéutico , Dolor/tratamiento farmacológico , Convulsiones/tratamiento farmacológico , Animales , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/síntesis química , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Imidazolidinas/administración & dosificación , Imidazolidinas/síntesis química , Bases de Mannich/administración & dosificación , Bases de Mannich/síntesis química , Ratones , Estructura Molecular , Oxaliplatino , Dolor/inducido químicamente , Ratas , Convulsiones/inducido químicamente , Relación Estructura-ActividadRESUMEN
BACKGROUND: 5,5-Diphenylhydantoin (Phenytoin) is a well-known anticonvulsant and antiarrhythmic drug which may cause unwanted side effects. In order to avoid the adverse effects of phenytoin, especially on the central nervous and cardiovascular systems, two small series of amine derivatives (Mannich bases) and amide ones were designed containing ß-tetralinohydantoin system. In preliminary studies, some of arylpiperazinylmethyl derivatives with a ß-tetralinohydantoin moiety were effective in screening anticonvulsant tests in mice. METHODS: These new amine and amide derivatives of ß-tetralinohydantoin were evaluated in standard anticonvulsant screens (maximal electroshock (MES) or pentylenetetrazole (scPTZ) seizure tests) and their neurotoxicity was assessed in standardized rotarod tests. Additionally, due to structural features (a hydantoin ring), influence on antiarrhythmic activity, electrocardiogram components and blood pressure was tested in rats. RESULTS: The new N-Mannich bases were effective in maximal electroshock or pentylenetetrazole seizures screens; and the most interesting compound 4 (1-{[4-(1-phenyethyl)-piperazin-1-yl]methyl}-3',4'-dihydro-1'H,2H,5H-spiro[imidazolidine-4,2'-naphthalene]-2,5-dione) displayed anticonvulsant activity in both the aforementioned tests. Furthermore, compound 6, an amide derivative of ß-tetralinohydantoin, displayed significant antiarrhythmic activity in a barium chloride-induced arrhythmia model (ED50 16.3mg/kg), but it was devoid of anticonvulsant protection. None of the tested compounds affected the electrocardiogram components or blood pressure in normotensive rats. CONCLUSION: All new N-Mannich bases containing the ß-tetralinohydantoin system and 1-phenylalkylpiperazine were classified to Anticonvulsant Screening Program 1st class. In contrast, our results suggested that the introduction of an amide bond in the alkyl side chain of the ß-tetralinohydantoin system abolished the anticonvulsant activity, but not the antiarrhythmic one. However, further studies are required for a definitive conclusion.
Asunto(s)
Amidas/química , Antiarrítmicos/química , Antiarrítmicos/farmacología , Anticonvulsivantes/química , Anticonvulsivantes/farmacología , Bases de Mannich/química , Fenitoína/química , Animales , Antiarrítmicos/efectos adversos , Anticonvulsivantes/efectos adversos , Modelos Animales de Enfermedad , Diseño de Fármacos , Electrochoque/métodos , Masculino , Síndromes de Neurotoxicidad/etiología , Pentilenotetrazol/química , Ratas , Ratas Sprague-Dawley , Prueba de Desempeño de Rotación con Aceleración Constante/métodos , Convulsiones/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
BACKGROUND: Antiepileptic drugs are commonly used in non-epileptic disorders. For example, phenytoin and levetiracetam demonstrate analgesic properties in rodent models of pain. In order to enhance their antinociceptive activity, structural features of phenytoin and levetiracetam, such as imidazolidine-2,4-dione and amide bond in alkyl chain, were combined in one molecule. Furthermore, in preliminary studies, methoxyphenylpiperazinpropyl derivatives of imidazolidine-2,4-dione acted as antinociceptive agents in several rodent models of acute pain. METHODS: The final compounds and the reference drugs - levetiracetam and phenytoin were evaluated in the hot plate test to assess their antinociceptive activity in this acute pain model. Furthermore, for the analgesic active compounds the impact on animals' locomotor activity and motor performance were estimated and the affinity to serotonergic (5-HT1A, 5-HT7) and adrenergic (α1) receptors was determined. RESULTS: Three of the tested compounds: 7, 15 and 18 showed statistically significant antinociceptive properties at the dose of 30mg/kg. Among them, compound 18, 1-methyl-3-[1-(morpholin-4-yl)-1-oxobutan-2-yl]imidazolidine-2,4-dione, exhibited the most significant and long-lasting antinociceptive activity. Noteworthy, this activity was not associated with a negative effect on animals' motor functions. Serotonergic or adrenergic neurotransmission is not involved in this antinociceptive effect. CONCLUSION: Some amide derivatives of imidazolidine-2,4-diones possess antinociceptive properties in mice but further studies are needed to explain their mechanism of action and assess their toxicity.
Asunto(s)
Dolor Agudo/tratamiento farmacológico , Amidas/farmacología , Analgésicos/farmacología , Imidazolidinas/química , Amidas/síntesis química , Amidas/uso terapéutico , Analgésicos/síntesis química , Animales , Anticonvulsivantes/síntesis química , Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , Imidazolidinas/farmacología , Imidazolidinas/uso terapéutico , Locomoción/efectos de los fármacos , Masculino , Ratones , Dimensión del Dolor/efectos de los fármacos , Prueba de Desempeño de Rotación con Aceleración Constante , Relación Estructura-ActividadRESUMEN
A series of novel spirohydantoin derivatives with arylpiperazinylbutyl moiety were synthesized and evaluated for serotonin 5-HT1A, 5-HT2A, 5-HT7 and dopamine D2 receptors. Based on these data, four compounds were selected for further binding affinity assays on dopamine D1, D3, D4, and 5-HT2C, 5-HT6 as well as adrenergic α1 and α2C receptors, which are involved in various CNS diseases such as schizophrenia, anxiety and/or depression. The compound 14, 1-{4-[4-(2-metoxyphe-nyl)piperazin-1-yl]butyl}-3',4'-dihydro-2H,2'H,5H-spiro[imidazolidine-4,1'-naphthalene]-2,5-dione, with the most promising functional profile, mixed 5-HT2A/D2 antagonist and 5-HT1A partial agonist, was selected. In the mouse d-amphetamine-induced locomotor hyperactivity model, compound 14 produced antipsychotic-like activity, which is devoid of cataleptogenic effects and in the forced swim test in mice, it showed a significant antidepressant-like effect unlike the reference drug aripiprazole.
Asunto(s)
Ansiolíticos/farmacología , Antidepresivos/farmacología , Antipsicóticos/farmacología , Hidantoínas/farmacología , Imidazolidinas/farmacología , Piperazinas/farmacología , Animales , Ansiolíticos/síntesis química , Antidepresivos/síntesis química , Antipsicóticos/síntesis química , Ansiedad/tratamiento farmacológico , Ansiedad/fisiopatología , Aripiprazol/farmacología , Depresión/tratamiento farmacológico , Depresión/fisiopatología , Dextroanfetamina , Hidantoínas/síntesis química , Hipercinesia/inducido químicamente , Hipercinesia/tratamiento farmacológico , Hipercinesia/fisiopatología , Imidazolidinas/síntesis química , Masculino , Ratones , Piperazinas/síntesis química , Receptor de Serotonina 5-HT1A/química , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT2A/química , Receptor de Serotonina 5-HT2A/metabolismo , Receptores de Dopamina D2/química , Receptores de Dopamina D2/metabolismo , Receptores de Serotonina/química , Receptores de Serotonina/metabolismo , Relación Estructura-Actividad , NataciónRESUMEN
A computer aided ligand design study of imidazolidine-2,4-dione derivatives was conducted in order to obtain compounds with dual 5-HT(1A) receptor and serotonin transporter (SERT) affinity. According to molecular modeling results, series of Mannich bases were chosen and synthesized. Investigated compounds were tested for 5-HT(1A) , 5-HT(2A) , α(1) and SERT affinity. Two selected compounds (5, 9) were characterized in functional experiments and possessed a pharmacological profile which may enhance SERT blocking efficacy - 5-HT(1A) partial agonism and 5-HT(2A) antagonism in one molecule. Furthermore these compounds displayed satisfactory selectivity over adrenergic α(1) receptors. The most promising compounds, 5-arylimidazolidine-2,4-dione derivatives with 4-(3-chlorophenyl)piperazinylmethyl moiety were tested for antidepressant and anxiolytic activity. In particular, compound 5 (5-(2-methoxyphenyl)-3-{1-[4-(3-chlorophenyl)piperazin-1-yl]methyl}-imidazolidine-2,4-dione), tested in the forced swim test in mice, exhibited a favorable antidepressant-like profile without affecting spontaneous locomotor activity.
Asunto(s)
Ansiolíticos , Antidepresivos , Hidantoínas , Bases de Mannich , Receptor de Serotonina 5-HT1A/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Animales , Ansiolíticos/síntesis química , Ansiolíticos/química , Ansiolíticos/farmacología , Antidepresivos/síntesis química , Antidepresivos/química , Antidepresivos/farmacología , Sitios de Unión , Diseño Asistido por Computadora , Cricetinae , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Humanos , Hidantoínas/síntesis química , Hidantoínas/química , Hidantoínas/farmacología , Ligandos , Masculino , Bases de Mannich/síntesis química , Bases de Mannich/química , Bases de Mannich/farmacología , Ratones , Simulación del Acoplamiento Molecular , Estructura Molecular , Actividad Motora/efectos de los fármacos , Unión Proteica , Ratas , Receptor de Serotonina 5-HT2A/metabolismo , NataciónRESUMEN
Synthesis, physicochemical and anticonvulsant properties of new N-Mannich bases derived from 5-cyclopropyl-5-phenyl- and 5-cyclopropyl-5-(4-chlorophenyl)-imidazolidine-2,4-diones have been described. Initial anticonvulsant screening was performed using intraperitoneal (ip.) maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests. The neurotoxicity was determined applying the rotarod test. The in vivo results in mice showed that all compounds were effective especially in the MES screen. The quantitative evaluation after oral administration in rats showed that the most active was 5-cyclopropyl-5-phenyl-imidazolidine-2,4-dione (1) with ED(50) values of 5.76 mg/kg (MES) and 57.31 mg/kg (scPTZ). This molecule was more potent than phenytoin and ethosuximide which were used as reference antiepileptic drugs. Additionally compound 1 with ED(50) of 26.06 mg/kg in psychomotor seizure test (6-Hz) in mice showed comparable activity to new generation anticonvulsant - levetiracetam.
Asunto(s)
Anticonvulsivantes/síntesis química , Anticonvulsivantes/farmacología , Imidazolidinas/síntesis química , Imidazolidinas/farmacología , Bases de Mannich/síntesis química , Bases de Mannich/farmacología , Animales , Imidazolidinas/química , Masculino , Bases de Mannich/química , Ratones , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Synthesis, physicochemical and anticonvulsant properties of new N-Mannich bases 3-24 derived from 5-cyclopropyl-5-phenyl- and 5-cyclopropyl-5-(4-chlorophenyl)-hydantoins were described here. Initial anticonvulsant screening was performed using intraperitoneal (i.p.) maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizures tests. Selected derivatives were also screened in the 6-Hz test. The neurotoxicity was determined applying the rotorod test. The pharmacological results revealed that the majority of compounds were effective in MES and/or scPTZ tests. The quantitative studies after oral administration into rats showed that several molecules were more potent than phenytoin and ethosuximide which were used as reference antiepileptic drugs. From the whole series the most active was 3-[(4-phenylpiperazin-1-yl)-methyl]-5-cyclopropyl-5-phenyl-imidazolidine-2,4-dione (3) with the ED(50) value of 5.29 mg/kg in the MES test.
Asunto(s)
Anticonvulsivantes/síntesis química , Hidantoínas/química , Bases de Mannich/síntesis química , Administración Oral , Animales , Anticonvulsivantes/química , Anticonvulsivantes/uso terapéutico , Anticonvulsivantes/toxicidad , Modelos Animales de Enfermedad , Masculino , Bases de Mannich/química , Bases de Mannich/uso terapéutico , Bases de Mannich/toxicidad , Ratones , Estructura Molecular , Síndromes de Neurotoxicidad/etiología , Ratas , Ratas Sprague-Dawley , Convulsiones/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
The synthesis and anticonvulsant properties of new N-Mannich bases of [7,8-f]benzo-2-aza-spiro[4.5]decane-1,3-diones (5a-h) and [7,8-f]benzo-1,3-diaza-spiro[4.5]decane-2,4-diones (7a-h) were described. Initial anticonvulsant screening was performed using intraperitoneal (ip) maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizures tests. The neurotoxicity was determined applying the rotarod test. The majority of compounds were effective in the MES or/and scPTZ screen. The quantitative studies showed that several molecules were more potent than phenytoin, used as reference drug. Selected derivatives were screened in the 6-Hz test and also assessed for potential activity against nerve agents using the Pilocarpine Induced Status Prevention model. To explain the possible mechanism of anticonvulsant action, for chosen active derivatives, their influence on voltage-dependent Na(+) channel were tested in vitro.
Asunto(s)
Anticonvulsivantes/química , Anticonvulsivantes/uso terapéutico , Bases de Mannich/química , Bases de Mannich/uso terapéutico , Convulsiones/tratamiento farmacológico , Animales , Anticonvulsivantes/síntesis química , Electrochoque , Hidantoínas/síntesis química , Hidantoínas/química , Masculino , Bases de Mannich/síntesis química , Ratones , Pentilenotetrazol , Ratas , Ratas Sprague-Dawley , Convulsiones/inducido químicamente , Canales de Sodio/metabolismo , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Succinimidas/síntesis química , Succinimidas/químicaRESUMEN
The synthesis of 5-(cyclo)alkyl-5-phenyl- and 5-spiroimidazolidine-2,4-dione derivatives with an arylpiperazinylpropyl moiety (12-23) and their in vitro and in vivo pharmacological properties and molecular characteristics were described. The investigated compounds exhibited high affinity for 5-HT(1A) (13-22) and 5-HT(2A) (18, 20, 21, 23) receptors and diversified pharmacological profile. Compounds 17, 20 and 22 showed antagonistic, partial agonistic and agonistic activity, respectively, toward 5-HT(1A) receptor and they were investigated as potential antidepressants and/or anxiolytics. The most interesting compound 22 (1-[3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl]-3',4'-dihydro-2'H-spiro[imidazolidine-4,1'-naphthalene]-2,5-dione), a pre- and postsynaptic 5-HT(1A) receptor agonist produced an antidepressant-like effect, which was more pronounced than that of imipramine in the forced swim test in mice, without affecting locomotor activity. Moreover, compound 22 produced a weak anxiolytic-like effect in the four-plate test in mice. Molecular docking studies of compound 22 to the homology model of the 5-HT(1A) receptor showed that a 3',4'-dihydro-2'H-spiro[imidazolidine-4,1'-naphthalene]-2,5-dione moiety played an important role in stabilizing the ligand-receptor complex.
Asunto(s)
Ansiolíticos/síntesis química , Ansiolíticos/farmacología , Antidepresivos/síntesis química , Antidepresivos/farmacología , Imidazolidinas/síntesis química , Imidazolidinas/farmacología , Agonistas del Receptor de Serotonina 5-HT1 , Agonistas de Receptores de Serotonina/síntesis química , Agonistas de Receptores de Serotonina/farmacología , Animales , Ansiolíticos/química , Antidepresivos/química , Imidazolidinas/química , Espectroscopía de Resonancia Magnética , Ratones , Modelos Moleculares , Actividad Motora/efectos de los fármacos , Ratas , Agonistas de Receptores de Serotonina/químicaRESUMEN
A series of new 3-[4-(4-arylpiperazinyl)-butyl]-beta-tetralonohydantoins (8a-13a) were synthesized. The compounds exhibited high affinity for 5-HT(1A) receptors (K(i)=6 to 55 nM) combined with moderate-to-high 5-HT(2A) receptor affinities (K(i)=45 to 213 nM). The results of in vivo studies indicated that of the compounds tested, 3-[4-(4-phenylpiperazinyl)-butyl-beta-tetralonohydantoin (8a) showed features of full (pre- and postsynaptic) 5-HT(1A) receptor agonists, whereas compounds 9a-13a behaved like antagonists of postsynaptic 5-HT(1A) receptors; additionally, compound 13a produced an effect characteristic of presynaptic 5-HT(1A) receptor agonists. Moreover, compounds 8a and 10a-13a exhibited properties of 5-HT(2A) receptor antagonists. Due to the most interesting 5-HT(1A)/5-HT(2A) functional profile compounds 8a and 13a were further tested for their potential psychotropic activity. In fact, compound 8a (but not 13a) showed diazepam-like anxiolytic activity and behaved like a weak antidepressant.
Asunto(s)
Hidantoínas/química , Hidantoínas/síntesis química , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT2A/metabolismo , Antagonistas de la Serotonina/síntesis química , Agonistas de Receptores de Serotonina/síntesis química , Animales , Ansiolíticos/síntesis química , Ansiolíticos/química , Ansiolíticos/farmacología , Antidepresivos/síntesis química , Antidepresivos/química , Antidepresivos/farmacología , Evaluación Preclínica de Medicamentos , Ratones , Ratas , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Antagonistas de la Serotonina/química , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/química , Agonistas de Receptores de Serotonina/farmacología , Relación Estructura-ActividadRESUMEN
Chromatographic parameters (deltaR(f)), defined as a difference in the migration of tested compound on the control and peptide impregnated silica gel TLC plates, were determined for 42 arylpiperazine derivatives. An amino acid sequence of the peptide used for impregnation was derived from the III transmembrane segment of the 5-HT(1A) receptor in the close vicinity of aspartic acid (Asp 166) residue. It was found that the deltaR(f) values obtained in a model employing tetrapeptide P4LA (ADVL), as well as the calculated logP correlate with 5-HT(1A) receptor affinity of the studied compounds.