2′,4′-二氯苯基哒嗪衍生物的抗小鼠癫痫作用

本文对2′,4′-二氯苯基哒嗪衍生物对几种实验性癫痫模型的对抗作用进行了研究,其中化合物Ⅰ和Ⅱ对最大电休克发作实验(MEST),戊四唑(Met)印防己毒素发作和荷包牡丹碱发作等四种实验性癫痫模型均有很强的对抗作用,强于苯妥英钠,苯巴比妥和卡马西平,但也显示中枢抑制作用,预防指数不高,化合物Ⅲ和Ⅳ对这四种动物惊厥模型亦有较强的对抗作用,均大大强于丙戊酸钠和乙琥胺,其中化合物Ⅲ的中枢神经系统毒性较低,抗MEST的预防指数高达23.4.     

6-取代苯基-3(2H)哒嗪酮的合成、抗惊活性及其构效关系的研究

本文报道了14个6-取代苯基-4,5-二氢-3(2H)哒嗪酮和15个6-取代苯基-3(2H)哒嚎酮的合成及其抗电惊活性。其ED50值表明,以2′,4′-二氯苯基-3(2H)哒嗪酮的抗惊作用为最强。构效分析表明,苯环上的取代基对化合物的抗惊活性有明显影响,吸电子取代基和疏水性参数值较大的取代基有利于提高化合物的抗惊活性。     

6-取代苯基-3(2H)哒嗪酮的合成、抗惊活性及其构效关系的研究

本文报道了14个6-取代苯基-4,5-二氢-3(2H)哒嗪酮和15个6-取代苯基-3(2H)哒嚎酮的合成及其抗电惊活性。其ED₅₀值表明,以2′,4′-二氯苯基-3(2H)哒嗪酮的抗惊作用为最强。构效分析表明,苯环上的取代基对化合物的抗惊活性有明显影响,吸电子取代基和疏水性参数值较大的取代基有利于提高化合物的抗惊活性。     

6-取代苯基哒嗪的3位γ-氨基丁酸衍生物的合成及抗惊活性

GABA的合成类似物是开发新型抗惊剂和抗癫痫药物的新领域。由芳香醛与吗啉、氰化钾反应形成的α-芳基-α-(4-吗啉)乙腈,可对α,β-不饱和腈或酯进行1,4-加成,生成1,4-酮酸型化合物。此物与肼缩合,再经芳构化即得6-芳基-3(2H)哒嗪酮。后者再经氯化后。与GABA缩合,制备3-(N-GABA)-6-芳基哒嗪类及其分子内脱水产物3-(N-丁内酰胺)-6-芳基哒嗪类化合物。本文应用此法合成了17个上述苯代哒嗪的GABA衍生物,并初步测验了它们的抗惊(MES)活性。活性最强的是3-(N-GABA)-6-(2′,4′-二氯苯基)哒嗪(ED₅₀=21.05mg/kg)。     

6-取代苯基哒嗪的3位γ-氨基丁酸衍生物的合成及抗惊活性

GABA的合成类似物是开发新型抗惊剂和抗癫痫药物的新领域。由芳香醛与吗啉、氰化钾反应形成的α-芳基-α-(4-吗啉)乙腈,可对α,β-不饱和腈或酯进行1,4-加成,生成1,4-酮酸型化合物。此物与肼缩合,再经芳构化即得6-芳基-3(2H)哒嗪酮。后者再经氯化后。与GABA缩合,制备3-(N-GABA)-6-芳基哒嗪类及其分子内脱水产物3-(N-丁内酰胺)-6-芳基哒嗪类化合物。本文应用此法合成了17个上述苯代哒嗪的GABA衍生物,并初步测验了它们的抗惊(MES)活性。活性最强的是3-(N-GABA)-6-(2′,4′-二氯苯基)哒嗪(ED_(50)=21.05mg/kg)。     

血吸虫病化学治疗的研究 ⅩⅩⅩⅥ.4-苯基(或烯丙基)-5-(吡嗪-2)-1,2,4-三唑-3-硫酮衍生物的合成

本文报导28个4-苯基(或烯丙基)-5-(吡嗪-2)-1,2,4-三唑-3-硫酮衍生物的合成。这类化合物的合成是以吡嗪甲酸乙酯与水合肼反应得2-吡嗪甲酰肼,再与不同的异硫氰酸酯作用后,在2N氢氧化钠溶液中环合而得Ⅱ或Ⅲ,然后经烷化、酰化及Mannich反应,分别制得相应的化合物。其中Ⅲ_1和Ⅲ_2对感染日本血吸虫小白鼠有明显肝移作用。     

血吸虫病化学治疗的研究 ⅩⅩⅩⅥ.4-苯基(或烯丙基)-5-(吡嗪-2)-1,2,4-三唑-3-硫酮衍生物的合成

本文报导28个4-苯基(或烯丙基)-5-(吡嗪-2)-1,2,4-三唑-3-硫酮衍生物的合成。这类化合物的合成是以吡嗪甲酸乙酯与水合肼反应得2-吡嗪甲酰肼,再与不同的异硫氰酸酯作用后,在2N氢氧化钠溶液中环合而得Ⅱ或Ⅲ,然后经烷化、酰化及Mannich反应,分别制得相应的化合物。其中Ⅲ₁和Ⅲ₂对感染日本血吸虫小白鼠有明显肝移作用。     

6,7-亚甲二氧基-1(2H,4H)-吖啶酮衍生物的合成及镇痛作用

报道13个6,7-亚甲二氧基-1(2H,4H)-吖啶酮衍生物的合成。初步药理实验表明:合成的化合物均有不同程度的镇痛作用,其中化合物Ⅱe的镇痛效力最强。     

4-(4-甲氧基苯基)-3,4-二氢-2(1H)-喹啉酮的合成及抗惊厥作用研究

目的筛选抗惊厥活性的化合物,寻找新型抗癫痫药物。方法以肉桂酸为原料,对其化学结构进行优化,合成了4-(4-甲氧基苯基)-3,4-二氢-2(1H)-喹啉酮。采用最大电休克发作实验(MES)测定其抗癫痫活性。结果采用红外光谱、核磁共振氢谱和质谱确定了化学结构。经药理活性筛选发现4-(4-甲氧基苯基)-3,4-二氢-2(1H)-喹啉酮具有抗惊厥作用。结论本合成路线简单、产物易分离,为开发新的抗癫痫药物提供了新思路。     

血吸虫病化学治疗的研究——ⅩⅩⅩⅦ.β-(5-硝基-4-溴-2-呋喃)-及β-(4,5-二溴-2-呋喃)丙烯酰胺及其酯类的合成

本文报道β-(4,5-二溴-2-呋喃)-及β-(5-硝基-4-溴-2-呋喃)丙烯酰胺及其酯类衍生物26个的合成。动物筛选结果表明;化合物Ⅲ_(?)。,Ⅲ_6和Ⅲ_(13)对感染日本血吸虫小白鼠有明显的治疗作用。化合物Ⅱ_(?)有较明显的预防作用。     

Anticonvulsant activity of (+)-5-methyl-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine (MK-801), a substance with potent anticonvulsant,central sympathomimetic,and apparent anxiolytic properties

MK-801 prevented tonic extensor seizures in the rat induced by bicuclline with the ED₅₀ being 23 μg/kg p.o. Clonazepam, phenobarbital, diazepam, phenytoin, γ-acetylenic GABA, sodium valproate, and trimethadione were all less potent. In mice, MK-801 was likewise the most potent (ED₅₀ = 0.35 mg/kg p.o.) compound in protecting against tonic seizures induced by electroshock. Clonazepam (ED₅₀ = 0.41 mg/kg p.o.) and MK-801 (ED₅₀ = 0.67 mg/kg p.o.) were by far more potent than any of the other anticonvulsants tested versus bicuculline-elicited seizures in mice. Besides being a potent anticonvulsant, MK-801 demonstrated selectivity, since much higher doses were required in mice to block clonic convulsions produced by pentylenetetrazol (ED₅₀ = 11 mg/kg p.o.) and tonic seizures caused by strychnine (ED₅₀ > 15 mg/kg p.o.) than were needed against electroshock or bicuculline. The anticonvulsant (electroshock) effect of MK-801 in mice was unaffected by pretreating the animals with various receptor antagonists (atropine, mecamylamine, chlorpheniramine, tripelennamine, cyproheptadine, cinanserin, methysergide, cimetidine, and propranolol). MK-801 was slightly, but significantly, antagonized by methergoline, naloxone, and theophylline, whereas haloperidol and especially α-adrenoceptor blockers (prazosin, HEAT, phenoxybenzamine) markedly reduced the anticonvulsant effect of MK-801. Haloperidol was selective for MK-801, not affecting the anticonvulsant actions of phenytoin or phenobarbital. Prazosin antagonized phenytoin and phenobarbital, but to a much lesser extent than it antagonized MK-801. MK-801 is an extremely potent and selective anticonvulsant acting at least partly via a catecholaminergic mechanism.     

Denzimol, a new anticonvulsant drug. I. General anticonvulsant profile

The anticonvulsant profile of N-[beta-[4-(beta-phenylethyl)phenyl]-beta-hydroxyethyl]imidazole hydrochloride (denzimol, Rec 15-1533) has been evaluated in mice, rats and rabbits in comparison with some standard antiepileptic drugs. Denzimol suppressed electrically and chemically induced tonic seizures but did not prevent the clonic ones. In mice and rabbits the anticonvulsant activity of denzimol against maximal electroshock seizures was almost equal to that of phenytoin and phenobarbital with more rapid onset of action, whereas in rats the compound resulted in being the most potent and the less toxic one showing a longer duration of anticonvulsant activity than phenytoin. In the maximal pentetrazol seizures test in rats denzimol showed a profile similar to that of phenytoin and carbamazepine, but different from that of barbiturates and benzodiazepines so that it is suggested that its clinical application would be that of "grand mal" and psychomotor type seizures therapy.     

Anticonvulsant activity of some 4-aminobenzanilides

A series of 4-aminobenzanilides derived from ring-alkylated anilines were prepared and evaluated for anticonvulsant activity. These benzanilides were prepared in the course of studies designed to determine the relationship between the benzamide structure and anticonvulsant effects. The compounds were tested in mice against seizures induced by electroshock and metrazole (pentylenetetrazole) and in the rotorod assay for neurologic deficit. All of the 4-aminobenzanilides showed activity at doses of 300 mg/kg against maximal electroshock seizures (MES). The 4-aminobenzanilide derived from 2,6-dimethylaniline (8) was the most potent anti-MES compound with an ED50 of 2.60 mg/kg and a protective index of 5.77 (PI = TD50/ED50). The activity profile for 8 compares quite favorably with that for phenobarbital and phenytoin in the same assays.     

Imperatorin enhances the protective activity of conventional antiepileptic drugs against maximal electroshock-induced seizures in mice

The effects of imperatorin (8-isopentenyloxypsoralen; 9-(3-methylbut-2-enyloxy)-7H-furo[3,2-g]chromen-7-one) on the anticonvulsant activity of four conventional antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) were studied in the mouse maximal electroshock seizure model. Results indicate that imperatorin (30 and 40 mg/kg, i.p.) significantly potentiated the anticonvulsant activity of carbamazepine against maximal electroshock-induced seizures by reducing its median effective dose (ED(50)) from 10.3 to 6.8 (by 34%; P<0.05) and 6.0 mg/kg (by 42%; P<0.01), respectively. Similarly, imperatorin (40 mg/kg, i.p.) markedly enhanced the antielectroshock action of phenobarbital and phenytoin, by lowering their ED(50) values from 19.6 to 12.2 mg/kg (by 38%; P<0.05-phenobarbital) and from 12.8 to 8.5 mg/kg (by 34%; P<0.05-phenytoin) in the maximal electroshock seizure test. In contrast, imperatorin (40 mg/kg, i.p.) did not affect the protective action of valproate against maximal electroshock-induced seizures in mice. Imperatorin at lower doses of 20 and 30 mg/kg had no significant effect on the anticonvulsant activities of conventional antiepileptic drugs in the mouse maximal electroshock seizure model. Pharmacokinetic evaluation of interaction between imperatorin (30 mg/kg, i.p.) and carbamazepine (6.8 mg/kg, i.p.) revealed a significant increase in total brain carbamazepine concentration after imperatorin administration, indicating a pharmacokinetic nature of interaction between these drugs. In cases of phenobarbital and phenytoin, imperatorin (40 mg/kg, i.p.) did not alter significantly total brain concentrations of phenytoin and phenobarbital in mice, and thus, the observed interactions in the maximal electroshock seizure test between imperatorin and phenobarbital or phenytoin were pharmacodynamic in nature. The present study demonstrates that imperatorin enhanced the antiseizure effects of carbamazepine, phenobarbital and phenytoin in the mouse maximal electroshock seizure model. However, the combination of imperatorin with carbamazepine, despite its beneficial effects in terms of seizure suppression in mice, was complicated by a pharmacokinetic increase in total brain carbamazepine concentration in experimental animals. In contrast, the combinations of imperatorin with phenytoin and phenobarbital, due to their beneficial antiseizure effects and no pharmacokinetic interactions between drugs in the brain compartment of experimental animals, deserve more attention and are of pivotal importance for epileptic patients as advantageous combinations from a clinical viewpoint.     

Are neuronal nicotinic receptors a target for antiepileptic drug development? Studies in different seizure models in mice and rats

Altered function of neuronal nicotinic acetylcholine receptors in the brain has recently been associated with an idiopathic form of partial epilepsy, suggesting that functional alterations of these receptors can be involved in the processes leading to epileptic seizures. Thus, nicotinic acetylcholine receptors may form a novel target for antiepileptic drug development. In the present study, various nicotinic acetylcholine receptor antagonists, including novel amino-alkyl-cyclohexane derivatives, were evaluated in two animal models, namely the maximal electroshock seizure test in mice and amygdala-kindling in rats. For comparison with these standard models of generalized and partial seizures, the effects against nicotine-induced seizures were examined. Because some of the agents tested showed an overlap between channel blocking at nicotinic acetylcholine receptors and NMDA receptors, the potency at these receptors was assessed by using patch clamp in a hippocampal cell preparation. Preferential nicotinic acetylcholine receptor antagonists were potent anticonvulsants in the maximal electroshock seizure test and against nicotine-induced seizures. The anticonvulsant potency in the maximal electroshock seizure test was decreased by administration of a subconvulsant dose of nicotine. Such a potency shift was also seen with selective NMDA receptor antagonists, which were also efficacious anticonvulsants against both maximal electroshock seizures and nicotine-induced seizures. Experiments with agents combining nicotinic acetylcholine receptor and NMDA receptor antagonistic effects suggested that both mechanisms contributed to the anticonvulsant effect of the respective agents in the maximal electroshock seizure test. This was not found in kindled rats, in which nicotinic acetylcholine receptor antagonists exerted less robust effects. In conclusion, it may be suggested that nicotinic acetylcholine receptor antagonism might be a valuable therapeutic approach to treat generalized epileptic seizures but rather not complex partial seizures.     

Anticonvulsant activity of delta9-tetrahydrocannabinol compared with three other drugs.

Delta9-tetrahydrocannabinol (THC) was compared with diphenylhydantoin (DPH), phenobarbital (PB) and chlordiazepoxide (CDP) using several standard laboratory procedures to determine anticonvulsant activity in mice, i.e., the maximal electroshock test (MES), and seizures induced by pentylenetetrazol, strychnine and nicotine. In the MES test, THC was the least potent and DPH the most potent blocker of hind limb tonic extensor convulsions whereas THC was the most potent and DPH the least potent in increasing the latency to this response and in preventing mortality. Seizures and mortality induced by pentylenetetrazol or by strychnine were enhanced by THC and DPH and were blocked by PB and CDP. In the test with nicotine, none of the four anticonvulsant agents prevented seizures; DPH was the only one which failed to increase latency; THC and DPH were less potent than PB and CDP in preventing mortality. THC most closely resembled DPH in the tests with chemical convulsant agents, but a sedative action of THC, resembling that of PB and CDP, was indicated by low ED5 0 for increased latency and for prevention of mortality in the MES test.     

N-phenyl-N'-pyridinylureas as anticonvulsant agents

A series of N-phenyl-N'-pyridinylureas was examined for anticonvulsant activity. Extensive structure/activity investigations revealed optimal activity in the N-(2,6-disubstituted-phenyl)-N'-(4-pyridinyl)urea series, with 37 exhibiting the best overall anticonvulsant profile. Compound 37 was effective against seizures induced by maximal electroshock but did not protect mice from clonic seizures produced by the convulsant pentylenetetrazol. The overall pharmacological profile suggests that 37 would be of therapeutic use in the treatment of generalized tonic-clonic and partial seizures. Compound 37 was selected for Phase 1 clinical trials.     

Synthesis and Anticonvulsant Activity of Ethyl 2,2‐dimethyl‐1‐(2‐substitutedhydrazinecarboxamido) Cyclopropanecarboxylate Derivatives

In this study on the development of new anticonvulsants, fourteen ethyl 2,2‐dimethyl‐1‐(2‐substitutedhydrazinecarboxamido) cyclopropanecarboxylate derivatives were synthesized and tested for anticonvulsant activity using the maximal electroshock, subcutaneous pentylenetetrazole screens, which are the most widely employed seizure models for early identification of candidate anticonvulsants. Their neurotoxicity was determined applying the rotorod test. Two compounds 6f and 6k showed promising anticonvulsant activities in both models employed for anticonvulsant evaluation. The most active compound 6k showed the maximal electroshock‐induced seizures with ED₅₀ value of 9.2 mg/kg and TD₅₀ value of 387.5 mg/kg after intraperitoneally injection to mice, which provided compound 6k with a protective index (TD₅₀/ED₅₀) of 42.1 in the maximal electroshock test.