RESUMEN
Chronic pain is a multifactorial disease comprised of both inflammatory and neuropathic components that affect â¼20% of the world's population. sec-Butylpropylacetamide (SPD) is a novel amide analogue of valproic acid (VPA) previously shown to possess a broad spectrum of anticonvulsant activity. In this study, we defined the pharmacokinetic parameters of SPD in rat and mouse, and then evaluated its antinociceptive potential in neuropathic and acute inflammatory pain models. In the sciatic nerve ligation (SNL) model of neuropathic pain, SPD was equipotent to gabapentin and more potent than its parent compound VPA. SPD also showed either higher or equal potency to VPA in the formalin, carrageenan, and writhing tests of inflammatory pain. SPD showed no effects on compound action potential properties in a sciatic nerve preparation, suggesting that its mechanism of action is distinct from local anesthetics and membrane stabilizing drugs. SPD's activity in both neuropathic and inflammatory pain warrants its development as a potential broad-spectrum anti-nociceptive drug.
Asunto(s)
Amidas/farmacología , Neuralgia/tratamiento farmacológico , Dolor/tratamiento farmacológico , Ácido Valproico/análogos & derivados , Ácido Valproico/farmacología , Aminas/farmacología , Analgésicos/farmacología , Animales , Ácidos Ciclohexanocarboxílicos/farmacología , Modelos Animales de Enfermedad , Gabapentina , Inflamación/complicaciones , Masculino , Ratones , Dolor/etiología , Ratas , Ratas Sprague-Dawley , Nervio Ciático/efectos de los fármacos , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
BACKGROUND: Though migraine is disabling and affects 12%-15% of the population, there are few drugs that have been developed specifically for migraine prevention. Valproic acid (VPA) is a broad-spectrum antiepileptic drug (AED) that is also used for migraine prophylaxis, but its clinical use is limited by its side effect profile. sec-Butylpropylacetamide (SPD) is a novel VPA derivative, designed to be more potent and tolerable than VPA, that has shown efficacy in animal seizure and pain models. METHODS: We evaluated SPD's antimigraine potential in the cortical spreading depression (CSD) and nitroglycerin (NTG) models of migraine. To evaluate SPD's mechanism of action, we performed whole-cell recordings on cultured cortical neurons and neuroblastoma cells. RESULTS: In the CSD model, the SPD-treated group showed a significantly lower median number of CSDs compared to controls. In the NTG-induced mechanical allodynia model, SPD dose-dependently reduced mechanical sensitivity compared to controls. SPD showed both a significant potentiation of GABA-mediated currents and a smaller but significant decrease in NMDA currents in cultured cortical neurons. Kainic acid-evoked currents and voltage-dependent sodium channel currents were not changed by SPD. CONCLUSIONS: These results demonstrate SPD's potential as a promising novel antimigraine compound, and suggest a GABAergic mechanism of action.
Asunto(s)
Amidas/uso terapéutico , Anticonvulsivantes/uso terapéutico , Trastornos Migrañosos/prevención & control , Trastornos Migrañosos/fisiopatología , Ácido Valproico/análogos & derivados , Amidas/farmacología , Animales , Anticonvulsivantes/farmacología , Línea Celular Tumoral , Células Cultivadas , Corteza Cerebral/citología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/fisiología , Depresión de Propagación Cortical/efectos de los fármacos , Depresión de Propagación Cortical/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ácido Valproico/farmacología , Ácido Valproico/uso terapéuticoRESUMEN
sec-Butylpropylacetamide (SPD) is a one-carbon homologue of valnoctamide (VCD), a chiral constitutional isomer of valproic acid's (VPA) corresponding amide--valpromide. Racemic-SPD and racemic-VCD possess a unique and broad-spectrum antiseizure profile superior to that of VPA. In addition, SPD blocks behavioral and electrographic status epilepticus (SE) induced by pilocarpine and the organophosphates soman and paraoxon. Valnoctamide has similar activity as SPD in the soman-induced SE model. The activity of SPD and VCD against SE is superior to that of diazepam and midazolam in terms of rapid onset, potency, and ability to block SE when given 20 to 60 min after seizure onset. sec-Butylpropylacetamide and VCD possess two stereogenic carbons in their chemical structure and, thus, exist as a racemic mixture of four individual stereoisomers. The anticonvulsant activity of the individual stereoisomers of SPD and VCD was comparatively evaluated in several anticonvulsant rodent models including the benzodiazepine-resistant SE model. sec-Butylpropylacetamide has stereoselective pharmacokinetics (PK) and pharmacodynamics (PD). The higher clearance of (2R,3S)-SPD and (2S,3R)-SPD led to a 50% lower plasma exposure and, consequently, to a lower anticonvulsant activity compared to racemic-SPD and its two other stereoisomers. Racemic-SPD, (2S,3S)-SPD, and (2R,3R)-SPD have similar anticonvulsant activities and PK profiles that are better than those of (2R,3S)-SPD and (2S,3R)-SPD. Valnoctamide has a stereoselective PK with (2S,3S)-VCD exhibiting the lowest clearance and, consequently, a twice-higher plasma exposure than all other stereoisomers. Nevertheless, there was less stereoselectivity in VCD anticonvulsant activity, and each stereoisomer had similar ED50 values in most models. sec-Butylpropylacetamide and VCD stereoisomers did not cause teratogenicity (i.e., neural tube defect) in mice at doses 3-12 times higher than their anticonvulsant-ED50 values. This article is part of a Special Issue entitled "Status Epilepticus".
Asunto(s)
Amidas/uso terapéutico , Anticonvulsivantes/uso terapéutico , Estado Epiléptico/tratamiento farmacológico , Ácido Valproico/análogos & derivados , Amidas/química , Animales , Anticonvulsivantes/química , Humanos , Estereoisomerismo , Ácido Valproico/química , Ácido Valproico/uso terapéuticoRESUMEN
OBJECTIVE: Valnoctamide (VCD), a central nervous system (CNS)-active chiral constitutional isomer of valpromide, the corresponding amide of valproic acid (VPA), is currently undergoing phase IIb clinical trials in acute mania. VCD exhibits stereoselective pharmacokinetics (PK) in animals and humans. The current study comparatively evaluated the pharmacodynamics (PD; anticonvulsant activity and teratogenicity) and PK of the four individual stereoisomers of VCD. METHODS: The anticonvulsant activity of VCD individual stereoisomers was evaluated in several rodent anticonvulsant models including maximal electroshock, 6 Hz psychomotor, subcutaneous metrazol, and the pilocarpine-induced and soman-induced status epilepticus (SE). The PK-PD (anticonvulsant activity) relationship of VCD stereoisomers was evaluated following intraperitoneal administration (70 mg/kg) to rats. Induction of neural tube defects (NTDs) by VCD stereoisomers was evaluated in a mouse strain that was highly susceptible to teratogen-induced NTDs. RESULTS: VCD had a stereoselective PK, with (2S,3S)-VCD exhibiting the lowest clearance, and consequently a twice-higher plasma exposure than all other stereoisomers. Nervertheless, there was less stereoselectivity in VCD anticonvulsant activity and each stereoisomer had similar median effective dose (ED)50 values in most models. VCD stereoisomers (258 or 389 mg/kg) did not cause NTDs. These doses are 3-12 times higher than VCD anticonvulsant ED50 values. SIGNIFICANCE: VCD displayed stereoselective PK that did not lead to significant stereoselective activity in various anticonvulsant rodent models. If VCD exerted its broad-spectrum anticonvulsant activity using a single mechanism of action (MOA), it is likely that it would exhibit a stereoselective PD. The fact that there was no significant difference between racemic VCD and its individual stereoisomers suggests that VCD's anticonvulsant activity is due to multiple MOAs.
Asunto(s)
Amidas/farmacocinética , Anticonvulsivantes/farmacocinética , Estimulantes del Sistema Nervioso Central/farmacocinética , Teratógenos/farmacocinética , Ácido Valproico/farmacocinética , Amidas/química , Amidas/toxicidad , Animales , Anticonvulsivantes/química , Anticonvulsivantes/toxicidad , Estimulantes del Sistema Nervioso Central/química , Estimulantes del Sistema Nervioso Central/toxicidad , Masculino , Ratones , Defectos del Tubo Neural/inducido químicamente , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Estado Epiléptico/inducido químicamente , Estado Epiléptico/prevención & control , Estereoisomerismo , Teratógenos/química , Teratógenos/toxicidad , Ácido Valproico/química , Ácido Valproico/toxicidadRESUMEN
sec-Butyl-propylacetamide (SPD) is a one-carbon homolog of valnoctamide (VCD), a chiral constitutional isomer of valproic acid's (VPA) corresponding amide valpromide. VCD has potential as a therapy in epilepsy including status epilepticus (SE) and neuropathic pain, and is currently being developed for the treatment of bipolar disorder. Both VCD and SPD possess two stereogenic carbons in their chemical structure. SPD possesses a unique and broad-spectrum antiseizure profile superior to that of valproic acid (VPA) and better than that of VCD. In addition SPD blocked behavioral- and electrographic-SE induced by pilocarpine and soman (organophosphate nerve gas) and afforded in vivo neuroprotection that was associated with cognitive sparing. VCD has activity similar to that of SPD in pilocarpine-induced status epilepticus (SE), although at higher doses. The activity of SPD and VCD against SE is superior to that of diazepam in terms of rapid onset, potency, and ability to block SE when given 20-60 min after seizure onset. When administered 20 and 40 min after SE onset, SPD (100-174 mg/kg) produced long-lasting efficacy (e.g., 4-8 h) against soman-induced convulsive and electrographic SE in both rats and guinea pigs. SPD activity in the pilocarpine and soman-induced SE models when administered 20-60 min after seizure onset, differentiates SPD from benzodiazepines and all other antiepileptic drugs .
Asunto(s)
Amidas/uso terapéutico , Anticonvulsivantes/uso terapéutico , Convulsiones/tratamiento farmacológico , Estado Epiléptico/tratamiento farmacológico , Ácido Valproico/análogos & derivados , Enfermedad Aguda , Amidas/química , Animales , Modelos Animales de Enfermedad , Cobayas , Humanos , Ratas , Convulsiones/inducido químicamente , Estado Epiléptico/inducido químicamente , Resultado del Tratamiento , Ácido Valproico/química , Ácido Valproico/uso terapéuticoRESUMEN
BACKGROUND: Valproic acid (VPA), widely used to treat epilepsy, bipolar disorders, and migraine prophylaxis, is known to cause neural tube and skeletal defects in humans and animals. Aminobenzensulfonamide derivatives of VPA with branched aliphatic carboxylic acids, namely 2-methyl-N-(4-sulfamoyl-phenyl)-pentanamide (MSP), 2-ethyl-N-(4-sulfamoyl-phenyl)-butyramide (ESB), 2-ethyl-4-methyl-N-(4-sulfamoyl-phenyl)-pentanamide (EMSP), and 2-ethyl-N-(4-sulfamoyl-benzyl)-butyramide (ESBB), have shown more potent anticonvulsant activity than VPA in preclinical testing. Here, we investigated the teratogenic effects of these analogous compounds of VPA in NMRI mice. METHODS: Pregnant NMRI mice were given a single subcutaneous injection of either VPA at 1.8 or 3.6 mmol/kg, or MSP, ESB, EMSP, or ESBB at 1.8, 3.6, or 4.8 mmol/kg on gestation day (GD) 8. Cesarean section was performed on GD 18, and the live fetuses were examined for external and skeletal malformations. RESULTS: Compared with VPA, which induced neural tube defects (NTDs) in fetuses at 1.8 and 3.6 mmol/kg, the analog derivatives induced no NTDs at dose levels up to 4.8 mmol/kg (except for a single case of exencephaly at 4.8 mmol/kg MSP). Skeletal examination showed several abnormalities mainly at the axial skeletal level with VPA at 1.8 mmol/kg. Fused vertebrae and/or fused ribs were also observed with MSP, ESB, EMSP, and ESBB, they were less severe and seen at a lower incidence that those induced by VPA at the same dose level. CONCLUSIONS: In addition to exerting more potent preclinical antiepileptic activity, teratology comparison indicates that aminobenzensulfonamide analogs are generally more weakly teratogenic than VPA.
Asunto(s)
Ácidos Carboxílicos/toxicidad , Anomalías Congénitas/patología , Ácidos Grasos/toxicidad , Sulfanilamidas/toxicidad , Sulfonamidas/toxicidad , Animales , Peso Corporal/efectos de los fármacos , Huesos/anomalías , Huesos/efectos de los fármacos , Huesos/patología , Ácidos Carboxílicos/química , Anomalías Congénitas/embriología , Embrión de Mamíferos/anomalías , Embrión de Mamíferos/efectos de los fármacos , Ácidos Grasos/química , Femenino , Ratones , Defectos del Tubo Neural/inducido químicamente , Defectos del Tubo Neural/embriología , Defectos del Tubo Neural/patología , Embarazo , Sulfanilamida , Sulfanilamidas/química , Sulfonamidas/química , Teratología , Ácido Valproico/análogos & derivados , Ácido Valproico/química , Ácido Valproico/toxicidadRESUMEN
sec-Butylpropylacetamide (racemic-SPD) is a chiral CNS-active amide derivative of valproic acid (VPA). This study describes synthesis and stereospecific comparative pharmacodynamics (PD, anticonvulsant activity and teratogenicity) and pharmacokinetic (PK) analysis of four individual SPD stereoisomers. SPD stereoisomers' anticonvulsant activity was comparatively evaluated in several anticonvulsant animal models including the benzodiazepine-resistant status epilepticus (SE). SPD stereoisomers' PK-PD relationship was evaluated in rats. Teratogenicity of SPD stereoisomers was evaluated in SWV mice strain, susceptible to VPA-induced neural tube defect (NTD). SPD stereoisomers (141 or 283 mg/kg) did not cause NTD. SPD has stereoselective PK and PD. (2R,3S)-SPD and (2S,3R)-SPD higher clearance led to a 50% lower plasma exposure that may contribute to their relative lower activity in the pilocarpine-induced SE model. (2S,3S)-SPD, (2R,3R)-SPD, and racemic-SPD have similar anticonvulsant activity and a PK profile that are better than those of (2R,3S)-SPD and (2S,3R)-SPD, making them good candidates for development as new, potent antiepileptics with a potential in benzodiazepine-resistant SE.
Asunto(s)
Acetamidas/uso terapéutico , Anticonvulsivantes/uso terapéutico , Estado Epiléptico/tratamiento farmacológico , Ácido Valproico/uso terapéutico , Acetamidas/farmacocinética , Acetamidas/farmacología , Amidas , Animales , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/farmacología , Modelos Animales de Enfermedad , Ratas , Soman/antagonistas & inhibidores , Estereoisomerismo , Teratógenos/toxicidad , Ácido Valproico/farmacocinética , Ácido Valproico/farmacologíaRESUMEN
PURPOSE: To determine the cytotoxicity of valproic acid (VPA) and its derivatives in human hepatoblastoma (HepG2) cells, and to study the possible toxicity of these compounds in human lymphocytes from patients with known hypersensitivity syndrome reactions (HSRs) to other medication. METHODS: Cells were exposed to physiological doses of VPA, valnoctamide (VCD) and its one carbon homologue sec-Butyl-propyl-acetamide (SPD) for 2h and for 24h. Cell viability was measured using succinate dehydrogenase activity for hepatocytes and lymphocyte toxicity assay (LTA) for lymphocytes. Cytokines and apoptosis [cytokeratine 18 (cCK18-M30)] markers were quantitated by ELISA. RESULTS: VCD and SPD presented lower cytotoxicity compared to VPA in cultured HepG2 cells. SPD led to cytotoxicity in lymphocytes. VPA and its derivatives increased the release of interferon (IFN)-γ and tumor necrosis factor (TNF)-α in media, but had no influence on the release of either interleukin (IL)-1 or IL-6. Significant increases in the release of IFN-γ and TNF-α were observed in lymphocytes exposed to high doses of VPA, and this increased further with exposure time. SIGNIFICANCE: HepG2 cells exposed to VCD and SPD experienced lower direct cytotoxicity than those treated with VPA. Lymphocytes from patients that experienced HSR to other medication have shown cytotoxicity to VPA and its VPA derivatives-induced. High levels of pro-inflammatory cytokines were released in the cell culture media, suggesting that inflammation plays a key role in VPA-derivatives induced lymphocyte toxicity.
Asunto(s)
Amidas/farmacología , Apoptosis/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Ácido Valproico/análogos & derivados , Ácido Valproico/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Síndrome de Hipersensibilidad a Medicamentos/inmunología , Síndrome de Hipersensibilidad a Medicamentos/metabolismo , Síndrome de Hipersensibilidad a Medicamentos/patología , Expresión Génica , Hepatocitos/citología , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Interferón gamma/biosíntesis , Interferón gamma/metabolismo , Interleucina-1/biosíntesis , Interleucina-1/metabolismo , Interleucina-6/biosíntesis , Interleucina-6/metabolismo , Queratina-18/genética , Queratina-18/metabolismo , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Linfocitos/patología , Transducción de Señal , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Propylisopropyl acetamide (PID) and valnoctamide (VCD) are two CNS-active constitutional isomers of valproic acid (VPA) corresponding amide (and prodrug) valpromide. VPA is a major antiepileptic drug (AED) used also in children. Consequently, the purpose of the current study was to see if PID, VCD and two of VCD stereoisomers are active also in juvenile anticonvulsant animal seizure models. Rat pups 7, 12, 18 and 25 days old were pretreated with PID, VCD or the VCD stereoisomers (2S,3S)-VCD, and (2R,3S)-VCD and 30 min later pentetrazol (100mg/kg s.c.) was administered. The incidence of seizures, their expression pattern and their latencies were registered and the severity was expressed by means of a five-point scale. All four tested compounds exhibited anticonvulsant activity against generalized tonic-clonic seizures. Lower doses suppressed specifically the tonic phase in 7-, 12- and 18-day-old rats, while higher doses abolished both phases of generalized seizures. This effect was most pronounced in 12-day-old rats. Twenty-five-day-old rats exhibited suppression of the entire pattern of generalized seizures. There were no significant differences among the drugs used. The CNS-active amide derivatives of VPA, VCD (racemate or individual stereoisomers) and PID exhibit potent anticonvulsant activity against generalized convulsive seizures in developing rats. The majority of these developmental effects are quantitative; while a specific selective action on the tonic phase of generalized seizures is the main qualitative change found in our study.
Asunto(s)
Anticonvulsivantes/farmacología , Convulsivantes , Pentilenotetrazol , Convulsiones/prevención & control , Ácido Valproico/análogos & derivados , Ácido Valproico/farmacología , Envejecimiento/fisiología , Alilisopropilacetamida/análogos & derivados , Alilisopropilacetamida/farmacología , Amidas/farmacología , Animales , Epilepsia Generalizada/inducido químicamente , Epilepsia Generalizada/prevención & control , Masculino , Ratas , Ratas Wistar , Convulsiones/inducido químicamente , EstereoisomerismoRESUMEN
A novel class of 19 carbamates was synthesized, and their anticonvulsant activity was comparatively evaluated in the rat maximal electroshock (MES) and subcutaneous metrazol (scMet) seizure tests and pilocarpine-induced status epilepticus (SE) model. In spite of the alkyl-carbamates' close structural features, only compounds 34, 38, and 40 were active at the MES test. The analogues 2-ethyl-3-methyl-butyl-carbamate (34) and 2-ethyl-3-methyl-pentyl-carbamate (38) also exhibited potent activity in the pilocarpine-SE model 30 min postseizure onset. Extending the aliphatic side chains of homologous carbamates from 7 to 8 (34 to 35) and from 8 to 9 carbons in the homologues 38 and 43 decreased the activity in the pilocarpine-SE model from ED(50) = 81 mg/kg (34) to 94 mg/kg (35) and from 96 mg/kg (38) to 114 mg/kg (43), respectively. The most potent carbamate, phenyl-ethyl-carbamate (47) (MES ED(50) = 16 mg/kg) contains an aromatic moiety in its structure. Compounds 34, 38, 40, and 47 offer the optimal efficacy-safety profile and, consequently, are promising candidates for development as new antiepileptics.
Asunto(s)
Anticonvulsivantes/síntesis química , Carbamatos/síntesis química , Animales , Anticonvulsivantes/farmacología , Anticonvulsivantes/toxicidad , Carbamatos/farmacología , Carbamatos/toxicidad , Masculino , Ratones , Síndromes de Neurotoxicidad/etiología , Ratas , Ratas Sprague-Dawley , Convulsiones/tratamiento farmacológico , Estado Epiléptico/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
Valproic acid (VPA) is the most widely prescribed epilepsy treatment worldwide, but its mechanism of action remains unclear. Our previous work identified a previously unknown effect of VPA in reducing phosphoinositide production in the simple model Dictyostelium followed by the transfer of data to a mammalian synaptic release model. In our current study, we show that the reduction in phosphoinositide [PtdInsP (also known as PIP) and PtdInsP(2) (also known as PIP(2))] production caused by VPA is acute and dose dependent, and that this effect occurs independently of phosphatidylinositol 3-kinase (PI3K) activity, inositol recycling and inositol synthesis. In characterising the structural requirements for this effect, we also identify a family of medium-chain fatty acids that show increased efficacy compared with VPA. Within the group of active compounds is a little-studied group previously associated with seizure control, and analysis of two of these compounds (nonanoic acid and 4-methyloctanoic acid) shows around a threefold enhanced potency compared with VPA for protection in an in vitro acute rat seizure model. Together, our data show that VPA and a newly identified group of medium-chain fatty acids reduce phosphoinositide levels independently of inositol regulation, and suggest the reinvestigation of these compounds as treatments for epilepsy.
Asunto(s)
Anticonvulsivantes/farmacología , Dictyostelium/efectos de los fármacos , Dictyostelium/metabolismo , Inositol/metabolismo , Fosfatidilinositoles/metabolismo , Ácido Valproico/farmacología , Animales , Anticonvulsivantes/química , Anticonvulsivantes/uso terapéutico , Dictyostelium/enzimología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Epilepsia/tratamiento farmacológico , Epilepsia/patología , Modelos Biológicos , Mutación/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Ratas , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Ácido Valproico/química , Ácido Valproico/uso terapéuticoRESUMEN
PURPOSE: sec-Butyl-propylacetamide (SPD) is a one-carbon homolog of valnoctamide (VCD), a central nervous system (CNS)-active amide derivative of valproic acid (VPA) currently in phase II clinical trials. The study reported herein evaluated the anticonvulsant activity of SPD in a battery of rodent seizure and epilepsy models and assessed its efficacy in rat and guinea pig models of status epilepticus (SE) and neuroprotection in an organotypic hippocampal slice model of excitotoxic cell death. METHODS: The anticonvulsant activity of SPD was evaluated in several rodent seizure and epilepsy models, including maximal electroshock (MES), 6-Hz psychomotor; subcutaneous (s.c.) metrazol-, s.c. picrotoxin, s.c. bicuculline, and audiogenic, corneal, and hippocampal kindled seizures following intraperitoneal administration. Results obtained with SPD are discussed in relationship to those obtained with VPA and VCD. SPD was also evaluated for its ability to block benzodiazepine-resistant SE induced by pilocarpine (rats) and soman (rats and guinea pigs) following intraperitoneal administration. SPD was tested for its ability to block excitotoxic cell death induced by the glutamate agonists N-methyl-D-aspartate (NMDA) and kainic acid (KA) using organotypic hippocampal slices and SE-induced hippocampal cell death using FluoroJade B staining. The cognitive function of SPD-treated rats that were protected against pilocarpine-induced convulsive SE was examined 10-14 days post-SE using the Morris water maze (MWM). The relationship between the pharmacokinetic profile of SPD and its efficacy against soman-induced SE was evaluated in two parallel studies following SPD (60 mg/kg, i.p.) administration in the soman SE rat model. KEY FINDINGS: SPD was highly effective and displayed a wide protective index (PI = median neurotoxic dose/median effective dose [TD(50)/ED(50)]) in the standardized seizure and epilepsy models employed. The wide PI values of SPD demonstrate that it is effective at doses well below those that produce behavioral impairment. Unlike VCD, SPD also displayed anticonvulsant activity in the rat pilocarpine model of SE. Thirty minutes after the induction of SE, the calculated rat ED(50) for SPD against convulsive SE in this model was 84 mg/kg. SPD was not neuroprotective in the organotypic hippocampal slice preparation; however, it did display hippocampal neuroprotection in both SE models and cognitive sparing in the MWM, which was associated with its antiseizure effect against pilocarpine-induced SE. When administered 20 and 40 min after SE onset, SPD (100-174 mg/kg) produced long-lasting efficacy (e.g., 4-8 h) against soman-induced convulsive and electrographic SE in both rats and guinea pigs. SPD ED(50) values in guinea pigs were 67 and 92 mg/kg when administered at SE onset or 40 min after SE onset, respectively. Assuming linear pharmacokinetics (PK), the PK-PD (pharmacodynamic) results (rats) suggests that effective SPD plasma levels ranged between 8 and 40 mg/L (20 min after the onset of soman-induced seizures) and 12-50 mg/L (40 min after the onset of soman-induced seizures). The time to peak (t(max)) pharmacodynamic effect (PD-t(max)) occurred after the PK-t(max), suggesting that SPD undergoes slow distribution to extraplasmatic sites, which is likely responsible for antiseizure activity of SPD. SIGNIFICANCE: The results demonstrate that SPD is a broad-spectrum antiseizure compound that blocks SE induced by pilocarpine and soman and affords in vivo neuroprotection that is associated with cognitive sparing. Its activity against SE is superior to that of diazepam in terms of rapid onset, potency, and its effect on animal mortality and functional improvement.
Asunto(s)
Anticonvulsivantes/farmacología , Anticonvulsivantes/farmacocinética , Convulsiones/tratamiento farmacológico , Estado Epiléptico/tratamiento farmacológico , Ácido Valproico/química , Amidas/química , Amidas/farmacocinética , Amidas/farmacología , Animales , Anticonvulsivantes/administración & dosificación , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Cobayas , Hipocampo/efectos de los fármacos , Masculino , Ratones , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , Resultado del Tratamiento , Ácido Valproico/análogos & derivados , Ácido Valproico/farmacocinética , Ácido Valproico/farmacologíaRESUMEN
A series of glycinamide conjugates and N-methoxy amide derivatives of valproic acid (VPA) analogs and constitutional isomers were synthesized and evaluated for anticonvulsant activity. Of all compounds synthesized and tested, only N-methoxy-valnoctamide (N-methoxy-VCD) possessed better activity than VPA in the following anticonvulsant tests: maximal electroshock, subcutaneous metrazol, and 6-Hz (32-mA) seizure tests. In mice, the ED(50) values of N-methoxy-VCD were 142 mg/kg (maximal electroshock test), 70 mg/kg (subcutaneous metrazol test), and 35 mg/kg (6-Hz test), and its neurotoxicity TD(50) was 118 mg/kg. In rats, the ED(50) of N-methoxy-VCD in the subcutaneous metrazol test was 36 mg/kg and its protective index (PI=TD(50)/ED(50)) was >5.5. In the rat pilocarpine-induced status epilepticus model, N-methoxy-VCD demonstrated full protection at 200mg/kg, without any neurotoxicity. N-Methoxy-VCD was tested for its ability to induce teratogenicity in a mouse strain susceptible to VPA-induced teratogenicity and was found to be nonteratogenic, although it caused some resorptions. Nevertheless, a safety margin was still maintained between the ED(50) values of N-methoxy-VCD in the mouse subcutaneous metrazol test and the doses that caused the resorptions. On the basis of these results, N-methoxy-VCD is a good candidate for further evaluation as a new anticonvulsant and central nervous system drug.
Asunto(s)
Amidas , Anticonvulsivantes/química , Anticonvulsivantes/uso terapéutico , Convulsiones/tratamiento farmacológico , Ácido Valproico , Amidas/química , Amidas/uso terapéutico , Animales , Convulsivantes/toxicidad , Modelos Animales de Enfermedad , Electrochoque/efectos adversos , Femenino , Isomerismo , Masculino , Ratones , Defectos del Tubo Neural/inducido químicamente , Pentilenotetrazol/toxicidad , Ratas , Ratas Sprague-Dawley , Convulsiones/etiología , Relación Estructura-Actividad , Ácido Valproico/análogos & derivados , Ácido Valproico/química , Ácido Valproico/uso terapéuticoRESUMEN
Aromatic amides comprising branched aliphatic carboxylic acids and 4-aminobenzenesulfonamide were evaluated for their inhibition of carbonic anhydrase (CA) isoforms. Of the most anticonvulsant-active compounds (2, 4, 13, 16, and 17), only 13, 16, and 17 were potent inhibitors of CAs VII and XIV. Compounds 9, 14, and 19 inhibited CA II, while 10 and 12 inhibited all isoforms. Structural studies suggest that differences in the active sites' hydrophobicity modulate the affinity of the inhibitors.
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Anticonvulsivantes/química , Anticonvulsivantes/farmacología , Inhibidores de Anhidrasa Carbónica/química , Inhibidores de Anhidrasa Carbónica/farmacología , Sulfonamidas/química , Sulfonamidas/farmacología , Anticonvulsivantes/síntesis química , Sitios de Unión , Inhibidores de Anhidrasa Carbónica/síntesis química , Anhidrasas Carbónicas/metabolismo , Cristalografía por Rayos X , Epilepsia/tratamiento farmacológico , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Isoformas de Proteínas/síntesis química , Isoformas de Proteínas/química , Isoformas de Proteínas/farmacología , Relación Estructura-Actividad , Sulfonamidas/síntesis químicaRESUMEN
PURPOSE: α-Fluoro-2,2,3,3-tetramethylcyclopropanecarboxamide (α-F-TMCD) and α-Cl-TMCD, are α-halo derivatives of TMCD, the corresponding amide of a cyclopropane analog of valproic acid (VPA). This study aimed to comparatively evaluate the pharmacodynamics and pharmacokinetics of α-F-TMCD and α-Cl-TMCD in rodent models of epilepsy and for antiepileptic drug (AED)-induced teratogenicity. The potential of α-F-TMCD as an antiallodynic and antinociceptive compound was also evaluated. METHODS: α-F-TMCD and α-Cl-TMCD were synthesized. α-Cl-TMCD anticonvulsant activity was evaluated in comparison to VPA in the mouse maximal-electroshock-seizure (MES), Metrazol (scMet), and 6-Hz psychomotor-seizure tests. Neurotoxicity was assessed by the Rotorod-ataxia test. Induction of neural tube defects (NTDs) by α-Cl-TMCD and α-F-TMCD was evaluated after intraperitoneal administration to a mouse strain highly susceptible to VPA-induced teratogenicity. The ability of α-F-TMCD to reduce pain was evaluated in the rat spinal nerve ligation (SNL) model for neuropathic pain and in the formalin test. α-F-TMCD and α-Cl-TMCD pharmacokinetics was evaluated following intraperitoneal (40 mg/kg) and oral (60 mg/kg) administration to rats. RESULTS: α-F-TMCD and α-Cl-TMCD had similar potencies in the 6-Hz test and were more potent than VPA in this model and in the scMet test. Neither induced NTDs, and both exhibited wide safety margins. α-F-TMCD was active in the two pain models, and was found to be equipotent to gabapentin in the SNL model (ED(50) = 37 and 32 mg/kg, respectively). Comparative pharmacokinetic analysis showed that α-Cl-TMCD is less susceptible to liver first-pass effect than α-F-TMCD because of lower total (metabolic) clearance and liver extraction ratio. CONCLUSIONS: Based on their potent anticonvulsant activity and lack of teratogenicity, α-F-TMCD and α-Cl-TMCD have the potential for development as new antiepileptics and central nervous system (CNS) drugs.
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Amidas/farmacología , Amidas/farmacocinética , Anticonvulsivantes/farmacología , Anticonvulsivantes/farmacocinética , Ciclopropanos/farmacología , Ciclopropanos/farmacocinética , Epilepsia/prevención & control , Ácido Valproico/análogos & derivados , Anomalías Inducidas por Medicamentos/etiología , Anomalías Inducidas por Medicamentos/prevención & control , Amidas/efectos adversos , Analgésicos/farmacocinética , Analgésicos/farmacología , Animales , Ciclopropanos/efectos adversos , Modelos Animales de Enfermedad , Humanos , Ratones , Defectos del Tubo Neural/inducido químicamente , Defectos del Tubo Neural/prevención & control , Dolor/prevención & control , Pentilenotetrazol/farmacología , Ratas , Ácido Valproico/farmacocinética , Ácido Valproico/farmacologíaRESUMEN
Despite the availability of 14 new antiepileptic drugs (AEDs), about 30% of epileptic patients are not seizure-free. Consequently there is substantial need to develop new effective AEDs. A novel class of aromatic amides composed of phenylacetic acid or branched aliphatic carboxylic acids, with five to nine carbons in their carboxylic moiety, and aminobenzenesulfonamide were synthesized and evaluated in the anticonvulsant rat-maximal electroshock (MES) and subcutaneous metrazol seizure (scMet) tests. Fourteen of the synthesized amides had an anticonvulsant ED(50) of <50 mg/kg in the rat-MES test. The amides 2-methyl-N-(4-sulfamoylphenyl)butyramide (10), 2-ethyl-N-(4-sulfamoylphenyl)butyramide (11), and 3,3-dimethyl-N-(4-sulfamoylphenyl)butyramide (15) were the most potent compounds possessing MES-ED(50) values of 7.6, 9.9, and 9.4 mg/kg and remarkable protective index (PI = TD(50)/ED(50)) values of 65.7, 50.5, and 53.2, respectively. These potent sulfanylamides caused neural tube defects only at doses markedly exceeding their effective dose. The anticonvulsant properties of these compounds make them potential candidates for further development as new, potent, and safe AEDs.
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Anilidas/síntesis química , Anticonvulsivantes/síntesis química , Defectos del Tubo Neural/inducido químicamente , Convulsiones/tratamiento farmacológico , Sulfonamidas/síntesis química , Anilidas/farmacología , Anilidas/toxicidad , Animales , Anticonvulsivantes/farmacología , Anticonvulsivantes/toxicidad , Convulsivantes , Electrochoque , Ratones , Pentilenotetrazol , Ratas , Ratas Sprague-Dawley , Convulsiones/etiología , Relación Estructura-Actividad , Sulfonamidas/farmacología , Sulfonamidas/toxicidadRESUMEN
The purpose of this study was to evaluate the stereoselective pain relieving (antiallodynic) activity, antiallodynic-anticonvulsant correlation, teratogenicity and pharmacokinetic profile of two stereoisomers of valnoctamide (VCD), a CNS-active amide derivative of a chiral isomer of valproic acid (VPA). The individual stereoisomers (diastereomers), (2R,3S)-VCD and (2S,3S)-VCD were synthesized and their antiallodynic activity was evaluated in rats using the spinal nerve ligation model of neuropathic pain. The pharmacokinetic profile of the two stereoisomers was evaluated in rats following: 1) i.p. administration of racemic-VCD, 2) i.p. administration of the individual stereoisomers (2R,3S)-VCD and (2S,3S)-VCD. Teratogenicity of racemic-VCD and its two individual stereoisomers was evaluated in a SWV mouse strain known to be highly susceptible to VPA-induced teratogenicity. Racemic-VCD, (2R,3S)-VCD and (2S,3S)-VCD showed a dose-related reversal of tactile allodynia with ED(50) values of 52, 61 and 39 mg/kg, respectively. (2S,3S)-VCD was significantly more potent than (2R,3S)-VCD but the opposite is true for its anticonvulsant-effect. In the teratogenicity evaluation racemic-VCD and its two individual stereoisomers showed mild embryotoxicity at doses 7-10 times higher than their antiallodynic-ED(50) values, while (2S,3S)-VCD was significantly less embryotoxic than (2R,3S)-VCD and racemic-VCD. Following administration of the racemic-VCD there was an increase in the primary pharmacokinetic parameters of (2S,3S)-VCD but not of (2R,3S)-VCD. This study demonstrates that both racemic-VCD and its stereoisomers show high potency as antiallodynic compounds and possess a wide safety margin. (2S,3S)-VCD is more potent and less embryotoxic than (2R,3S)-VCD and thus, has a potential to become a candidate for development as a new drug for treating neuropathic pain.
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Amidas/farmacología , Analgésicos/farmacología , Anticonvulsivantes/farmacología , Pérdida del Embrión/inducido químicamente , Defectos del Tubo Neural/inducido químicamente , Amidas/farmacocinética , Amidas/toxicidad , Analgésicos/farmacocinética , Analgésicos/toxicidad , Animales , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/toxicidad , Masculino , Ratones , Dolor/tratamiento farmacológico , Dolor/fisiopatología , Dimensión del Dolor , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , TactoRESUMEN
PURPOSE: The purpose of this study was to evaluate the stereoselective anticonvulsant activity, neurotoxicity, pharmacokinetics, and teratogenic potential of two stereoisomers of valnoctylurea (VCU), a central nervous system (CNS)-active urea derivative of valnoctic acid, which is a constitutional isomer of valproic acid (VPA). METHODS: VCU stereoisomers (2S,3S)-VCU and (2R,3S)-VCU were synthesized. Their anticonvulsant activity was determined and compared to VPA and racemic-VCU in rats utilizing the maximal electroshock seizure (MES) and the subcutaneous pentylenetetrazole (scMet) tests. Neurotoxicity was determined in rats using the positional sense test, muscle tone test, and gait and stance test. The induction of neural tube defects (NTDs) by VCU stereoisomers was evaluated in a mouse strain highly susceptible to VPA-induced teratogenicity. The pharmacokinetics of VCU was studied in a stereoselective manner following intraperitoneal (i.p.) administration to rats. RESULTS: (2S,3S)-VCU and (2R,3S)-VCU median effective dose ED(50) values were 29 mg/kg [95% confidence interval (CI) = 8-60 mg/kg] and 42 mg/kg (95% CI = 36-51 mg/kg) (MES) and 22 mg/kg (95% CI = 13-51 mg/kg) and 12 mg/kg (95%CI = 7-21 mg/kg) (scMet), respectively. (2S,3S)-VCU was more potent and had a wider safety margin (p < 0.05), defined as the protective index (PI = TD(50)/ED(50)), at both the MES (PI > 17) and scMet (PI > 23) tests than racemic-VCU or (R,S)-VCU (PI = 2.8 and 9.9, respectively). VCU stereoisomers caused NTDs at doses >4 times that of their anticonvulsant ED(50) values. At a dose of 112 mg/kg, (2R,3S)-VCU was nonteratogenic and less embryotoxic than its stereoisomer (2S,3S)-VCU. No stereoselective pharmacokinetics was observed following intraperitoneal dosing of racemic-VCU to rats. VCU was mainly eliminated by metabolism with a half-life of 2 h. CONCLUSIONS: VCU anticonvulsant activity and wide PI values make it a potential candidate for development as a new, potent antiepileptic drug (AED).
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Convulsiones/inducido químicamente , Urea/análogos & derivados , Animales , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/farmacología , Anticonvulsivantes/toxicidad , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Electrochoque/métodos , Femenino , Semivida , Masculino , Ratones , Defectos del Tubo Neural/inducido químicamente , Ácidos Pentanoicos/farmacocinética , Ácidos Pentanoicos/farmacología , Ácidos Pentanoicos/toxicidad , Pentilenotetrazol/farmacología , Embarazo , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Teratógenos/farmacología , Urea/farmacocinética , Urea/farmacología , Urea/toxicidad , Ácido Valproico/análogos & derivados , Ácido Valproico/farmacocinética , Ácido Valproico/farmacologíaRESUMEN
Valproic acid (VPA, 1) is a major broad spectrum antiepileptic and central nervous system drug widely used to treat epilepsy, bipolar disorder, and migraine. VPA's clinical use is limited by two severe and life-threatening side effects, teratogenicity and hepatotoxicity. A number of VPA analogues and their amide, N-methylamide and urea derivatives, were synthesized and evaluated in animal models of neuropathic pain and epilepsy. Among these, two amide and two urea derivatives of 1 showed the highest potency as antineuropathic pain compounds, with ED(50) values of 49 and 51 mg/kg for the amides (19 and 20) and 49 and 74 mg/kg for the urea derivatives (29 and 33), respectively. 19, 20, and 29 were equipotent to gabapentin, a leading drug for the treatment of neuropathic pain. These data indicate strong potential for the above-mentioned novel compounds as candidates for future drug development for the treatment of neuropathic pain.
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Amidas/química , Anticonvulsivantes/química , Anticonvulsivantes/farmacología , Dolor/tratamiento farmacológico , Urea/análogos & derivados , Ácido Valproico/química , Ácido Valproico/farmacología , Animales , Anticonvulsivantes/síntesis química , Anticonvulsivantes/uso terapéutico , Electrochoque , Isomerismo , Masculino , Ratones , Dolor/inducido químicamente , Pentilenotetrazol/farmacología , Ratas , Ratas Sprague-Dawley , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , Nervios Espinales , Ácido Valproico/síntesis química , Ácido Valproico/uso terapéuticoRESUMEN
BACKGROUND: Valproic acid (VPA) is used to treat epilepsy and bipolar disorders, as well as for migraine prophylaxis. However, its clinical use is limited by two life-threatening side effects: hepatotoxicity and teratogenicity. To develop a more potent and safer second-generation VPA drug, the urea derivatives of four VPA analogs (2-ethyl-3-methylpentanoyl urea, 2-ethylhexanoyl urea, 2-ethyl-4-methylpentanoyl urea, and 2-methylbutanoyl urea) were synthesized. METHODS: Four CNS-active analogs of a VPA urea derivative testedthe anticonvulsant activity in the maximal electroshock seizure test (MES) and subcutaneous metrazol seizure threshold test (scMet). Teratogenic effects of these compounds were evaluated in NMRI mice susceptible to VPA-induced teratogenicity by comparison with VPA. RESULTS: All four VPA analogs showed superior anticonvulsant activity over VPA. Compared with VPA, which induced neural tube defects (NTDs) in fetuses at 1.8 and 3.6 mmol/kg, the analog derivatives induced no NTDs at any concentration up to 4.8 mmol/kg (except for a single abnormality at 3.6 mmol/kg with 2-ethyl-3-methylpentanoyl urea). Skeletal examination also revealed that the acylurea derivatives induced vertebral and rib abnormalities in fetuses markedly less frequently than VPA. Our results confirmed that the analogue derivatives are significantly less teratogenic than VPA in NMRI mice. CONCLUSIONS: The CNS-active VPA analogs containing a urea moiety, which have better anticonvulsant potency and lack teratogenicity, are good potential candidates as second-generation VPA antiepileptic drugs.