Antiparkinsonian Activity Research Articles

Zonisamide for the treatment of Parkinson’s disease

Zonisamide is an antiepileptic drug widely used to treat seizures worldwide. In additrion to epilepsy, zonisamide may have beneficial efficacy in various neurological or psychiatric diseases. This article reviews the structure, mechanism of action, pharmacokinetics and possible antiparkinsonian action of zonisamide. A multicentered, randomized, double-blind, placebo-controlled study conducted in Japan provided data suggesting that zonisamide, as an add-on treatment, has efficacy in treating motor symptoms in patients with Parkinson’s disease (PD). Zonisamide may be effective in reducing the duration of ‘off’ time in patients with PD treated with L-DOPA. The therapeutic doses of zonisamide for the treatment of PD are 50–100 mg/day, considerably lower than those for the treatment of epilepsy (200–400 mg/day). It is expected that zonisamide will be safe and tolerated in patients with PD, as it has been used as an antiepileptic for more than 15 years; however, further studies are required to evaluate its safety and tolerability in the treatment of PD. The pharmacological mechanisms of the beneficial actions of zonisamide in PD remain unclear. Various hypotheses have been proposed, but the supporting data are not yet sufficient to draw any conclusions. Further basic research is required to advance our understanding of the antiparkinsonian mechanism of zonisamide.

Effect of acute administration of hydroalcohol extract of Ilex paraguariensis St Hilaire (Aquifoliaceae) in animal models of Parkinson's disease

Ilex paraguariensis St Hilaire (Aquifoliaceae) is a plant widely cultivated in South America and with various reputed medicinal properties that can be attributed to phenolic constituents of the leaves: caffeine, theophylline and theobromine, besides the flavonoids, quercetin and rutin. This study examined the antiparkinsonian activity of the hydroalcohol extract of Ilex paraguariensis in models of protection against cerebral injury induced by MPTP and reversal of the catatonia induced by reserpine in mice. The hydroalcohol extract prevented MPTP-induced hypolocomotion at doses of 250 and 500 mg/kg at the all time points observed and also prevented the reserpine-induced catalepsy at the same doses. The extract potentiated the effect of apomorphine in preventing catatonia, suggesting a non-dopaminergic activity, probably through antagonism of adenosine. In biochemical studies the hydroalcohol extract caused a significant decrease in the NO levels, exhibited a DPPH-scavenging ability and was effective in preventing the oxidation of deoxyribose. The results obtained suggest that the hydroalcohol extract of Ilex paraguariensis may have an antiparkinsonian profile in animal models, probably through its antioxidant activity and antagonist action on adenosine A(2A) receptors.

Blockade of Cannabinoid Type 1 Receptors Augments the Antiparkinsonian Action of Levodopa without Affecting Dyskinesias in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Treated Rhesus Monkeys

Drugs acting at cannabinoid type 1 receptors (CB1) have modulatory effects on glutamate and GABA neurotransmission in basal ganglia; thus, they potentially affect motor behavior in the parkinsonian setting. Preclinical trials with diverse cannabinoid agents have shown varied results, and the precise effects of blocking cannabinoid CB1 receptors remain uncertain. We tested behavioral effects of the selective antagonist 1-[7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a]-[1,3,5]triazin-4-yl]-3-ethylaminoazetidine-3-carboxylic acid amide benzenesulfonate (CE) as monotherapy and in combination with l-DOPA in treatment-naive and L-DOPA-primed 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated rhesus monkeys with moderate and severe parkinsonism. Motor disability and L-DOPA-induced dyskinesias were scored with a standardized scale after subcutaneous drug administration, and plasma levels of L-DOPA were determined by high-performance liquid chromatography/electrochemical detection. CE doses ranged from 0.03 to 1 mg/kg, and L-DOPA methyl ester doses were selected as optimal and suboptimal doses (maximal and 50% of maximal responses, respectively). CE had no intrinsic effects on motor behavior regardless of the degree of parkinsonism (moderate or severe groups) or previous drug exposure ("de novo" or after L-DOPA priming). Initial CE administration did not affect development of L-DOPA antiparkinsonian responses. In coadministration trials, CE, in a dose-dependent manner, increased responses to L-DOPA (suboptimal doses). These effects were seen in both moderate and severely parkinsonian monkeys as a 30% increase of, predominantly, response duration with no effects on L-DOPA pharmacokinetics. CE did not modify levodopa-induced dyskinesias. These results suggest that selective cannabinoid CB1 antagonists may enhance the antiparkinsonian action of dopaminomimetics and possibly facilitate the use of lower doses, thereby reducing side effects.

Synthesis, Analgesic, and Antiparkinsonian Profiles of Some Pyridine, Pyrazoline, and Thiopyrimidine Derivatives

A series of substituted pyridine, pyrazoline, and thiopyrimidine derivatives were synthesized from 3-acetylpyridine, which was prepared from nicotinic acid as a naturally starting material. The pharmacological screening showed that many of these compounds have good analgesic and antiparkinsonian activities comparable to Voltarene® and Benzatropine® as reference drugs. The structure assignment of the new compounds is based on chemical and spectroscopic evidence. The detailed synthesis, spectroscopic data, and pharmacological properties for synthesized compounds are reported.

Chronic SKF83959 induced less severe dyskinesia and attenuated L-DOPA-induced dyskinesia in 6-OHDA-lesioned rat model of Parkinson's disease

SKF83959, a recently identified selective agonist of putative phosphoinositide-linked (PI-linked) D 1 dopamine (DA) receptor, is found to elicit excellent anti-parkinsonism effects in monkeys and rodents. In the present study, the effects of SKF83959 on l-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) were assessed in a unilateral 6-hydroxydopamine (6-OHDA) lesioned rat model of Parkinson's disease (PD). The results indicated that chronic L-DOPA (6 mg/kg) induced a progressive dyskinesia-like behavior in PD rats, whereas SKF83959 (0.5 mg/kg) elicited significantly less severe dyskinesia while exerts its anti-parkinsonian action effectively. Application of D 1 receptor, but not D 2, α or 5-HT receptor antagonist attenuated SKF83959-induced dyskinesia, indicating that a D 1 receptor-mediated events, assumedly via PI-linked D 1 receptor. Interestingly, chronic co-administration of SKF83959 significantly reduced LID at no expanse of reduction in the anti-parkinsonian potency in PD rats. However, this anti-dyskinesia effect was not observed while SKF83959 was acutely administered in rats with established LID. This implies that chronic SKF83959 attenuated the development of dyskinesia. Immediate early gene FosB is previously reported to positively associate with dyskinesia. However, we found that the anti-dyskinesia effect of chronic SKF83959 was independent of FosB since SKF83959 produced stronger FosB expression in the lesioned striatum than that of L-DOPA while exerting its anti-dyskinesia action. The present data demonstrated that SKF83959 reduces LID by attenuating the development of dyskinesia; the underlying signaling pathway for the anti-dyskinesia action of SKF83959 appears not to depend on FosB.

Characterization of the antiparkinsonian effects of the new adenosine A 2A receptor antagonist ST1535: Acute and subchronic studies in rats

Antagonism of adenosine A 2A receptor function has been proposed as an effective therapy in the treatment of Parkinson's disease. Thus, the study of new adenosine receptor antagonists is of great importance for the potential use of these drugs in clinical practice. The present study evaluated effects of the new preferential adenosine A 2A receptor antagonist 2-butyl-9-methyl-8-(2 H-1,2,3-triazol-2-yl)-9 H-purin-6-ylamine (ST1535) in unilaterally 6-hydroxydopamine lesioned rats. Acute ST1535 dose-dependently potentiated contralateral turning behaviour induced by a threshold dose of l-3,4-dihydroxyphenylalanine ( l-DOPA) (3 mg/kg i.p.), a classical test for antiparkinson drug screening. Subchronic (18 days, twice a day) ST1535 (20 mg/kg i.p.) + l-DOPA (3 mg/kg i.p.) did not induce sensitization to turning behaviour or abnormal involuntary movements during the course of treatment, indicating a low dyskinetic potential of the drug. Moreover, while subchronic administration of a fully effective dose of l-DOPA (6 mg/kg i.p.) significantly increased GABA synthesizing enzyme glutamic acid decardoxylase (GAD67), dynorphin and enkephalin mRNA levels in the lesioned striatum, subchronic ST1535 (20 mg/kg i.p.) + l-DOPA (3 mg/kg i.p.) did not modify any of these markers, although it induced a similar number of contralateral rotations at the beginning of treatment. Finally, acute administration of ST1535 (20 mg/kg i.p.) proved capable of reducing jaw tremors in tacrine model of Parkinson's disease tremor. Results showed that ST1535, in association with a low dose of l-DOPA, displayed antiparkinsonian activity similar to that produced by a full dose of l-DOPA without exacerbating abnormal motor side effects. Moreover, in agreement to other well characterized adenosine A 2A receptor antagonists, ST1535 features antitremorigenic effects.

Plasma levels of rotigotine and the reversal of motor deficits in MPTP-treated primates

Rotigotine is a nonergolinic dopamine D3/D2/D1-receptor agonist used clinically for the treatment of Parkinson's disease. This study aimed to determine the relationship between peak antiparkinsonian activity and drug plasma levels after administration of rotigotine to 1-methyl-4-phenyl-1,2,3,6-tetrahydropytidine-treated primates. Using single subcutaneous injections of rotigotine and blood sampling at two subsequent time points, the relationship between improvement in motor activity and plasma rotigotine level was evaluated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropytidine-treated common marmosets. Rotigotine (0.01875-0.3 mg/kg subcutaneously) produced an increase in locomotor activity even at the lowest dose tested. Total increase in motor activity and duration of drug effect were dose related. Motor disability was similarly improved by rotigotine in a dose-dependent manner. At the highest doses, hyperactivity and stereotypy were observed. Plasma concentrations of rotigotine were linearly related to dose over dosage range employed, but not to behavioral response. Results show that pulsatile administration of rotigotine effectively normalizes motor activity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropytidine-treated marmosets. Although dose and plasma concentrations of rotigotine are closely related, drug effects in the brain measured as locomotion and improvement of disability dissociate from plasma levels. Plasma levels corresponding to the optimal dose range (0.01875-0.075 mg/kg) will guide a continuous administration regimen of rotigotine in a subsequent study using the same experimental model of Parkinson's disease.

The nociceptin/orphanin FQ receptor antagonist J-113397 and L-DOPA additively attenuate experimental parkinsonism through overinhibition of the nigrothalamic pathway.

By using a battery of behavioral tests, we showed that nociceptin/orphanin FQ receptor (NOP receptor) antagonists attenuated parkinsonian-like symptoms in 6-hydroxydopamine hemilesioned rats (Marti et al., 2005). We now present evidence that coadministration of the NOP receptor antagonist 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H benzimidazol-2-one (J-113397) and L-DOPA to 6-hydroxydopamine hemilesioned rats produced an additive attenuation of parkinsonism. To investigate the neurobiological substrates underlying this interaction, in vivo microdialysis was used in combination with behavioral measurements (bar test). J-113397 and L-DOPA alone reduced the time on bars (i.e., attenuated akinesia) and elevated GABA release selectively in the lesioned substantia nigra reticulata. J-113397 also reduced nigral glutamate levels, whereas L-DOPA was ineffective. J-113397 and L-DOPA coadministration produced additive antiakinetic effect, which was associated with additive increase in nigral GABA release but no additional reductions in glutamate levels. To investigate whether the increase in nigral GABA release could translate to changes in nigrothalamic transmission, GABA release was monitored in the ventromedial thalamus (one of the main target areas of the nigrothalamic projections). J-113397 and L-DOPA decreased thalamic GABA release and attenuated akinesia, their combination resulting in a more profound effect. These actions were prevented by perfusing the voltage-dependent Na+ channel blocker tetrodotoxin or the GABA(A) receptor antagonist bicuculline in the substantia nigra reticulata. These data demonstrate that J-113397 and L-DOPA exert their antiparkinsonian action through overinhibition of nigrothalamic transmission and suggest that NOP receptor antagonists may be useful as an adjunct to L-DOPA therapy for Parkinson's disease.

Antiparkinsonian activity of L-propyl-L-leucyl-glycinamide or melanocyte-inhibiting factor in MPTP-treated common marmosets

The neuropeptide melanocyte-inhibiting factor (MIF) or L-propyl-L-leucyl-glycinamide (PLG) has been reported in some studies to improve the motor signs of Parkinson's disease (PD) and in rodent models of PD. In this study of oral and intravenous MIF in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets, a wide range of doses of MIF administered alone (0.25, 1, 2, 5, 10, 20 mg/kg orally) did not increase locomotor activity, relieve motor disability, or induce dyskinesias. When MIF (1.0 and 5.0 mg/kg orally or 10 and 20 mg/kg intravenously) was administered concomitantly with levodopa/benserazide, no significant differences in motor function or dyskinesias were observed compared with levodopa/benserazide alone. The results of this first study of MIF in the marmoset MPTP model provide no encouragement for the reinvestigation of MIF in the clinical management of the motor signs of PD.

Synthesis of scopine 3-amino-2-phenylpropionate derivatives

The 8 azabicyclo[3.2.1]octane (tropane) fragment is found in some natural alkaloids (atropine, scopolamine, anatoxin, etc.).1—4 Like many other synthetic deriva tives of this heterocycle, they exhibit analgetic, hypoten sive, anti Parkinsonian, and methacholinolytic activities and are used in medical practice as chemotherapeutic drugs.5—10 In the present work, we developed a new method for the synthesis of scopine containing β amino acid deriva tives that may be of interest as physiologically active com pounds. The starting materials were scopolamine hydro bromide (1) and secondary amines such as diethyl amine (2a), piperidine (2b), and morpholine (2c). Heating of scopolamine hydrobromide 1 with diethyl amine 2a in the molar ratio 1 : 3 at 120 °C gave scopine 3 (N,N diethylamino) 2 phenylpropionate (3a) in ~10% yield. Reactions of scopolamine hydrobromide 1 with piperidine 2b and morpholine 2c were much more efficient: the yields of amino esters 3b and 3c were 88 and 70%, respectively. In all cases, racemization of the chiral center in the acid moiety of scopolamine took place. Under these conditions, the epoxide ring of scopolamine did not undergo opening in the presence of the aforemen tioned amines. In contrast to amines 2a—c, the reaction of L proline (2d) with scopolamine hydrobromide oc curred as esterification to give optically active scopine 2 phenyl 3 (pyrrolidin 2 ylcarbonyloxy)propionate (4) in 95% yield. When an aqueous solution of amine 2a or scopol amine rather than its hydrobromide 1 were used, the ester bond of scopolamine underwent very rapid hydrolysis to give scopoline (6 methyl 2 oxa 6 azatricyclo[3.3.1.03,7] nonan 4 ol) and tropic (3 hydroxy 2 phenylpropionic) acid.11 Interestingly, the reaction with isopropylamine yielded a complex mixture of products. Apparently, the formation of β amino acid esters 3a—c passes through the formation of scopine 2 phenylprop 2 enoate followed by the Michael addition of amines 2a—c to the activated C=C bond,12—14 which is evident from racemization of the optically active (–) S center of the acid fragment in scopolamine. In summary, we proposed a route to derivatives of scopine 3 amino 2 phenylpropionate via reactions of sco polamine hydrobromide with secondary amines. * Dedicated to Academician O. M. Nefedov on the occasion of his 75th birthday. Scheme 1

Receptor–receptor interactions as studied with microdialysis. Focus on NTR/D2 interactions in the basal ganglia

Using mono and dualprobe(s) microdialysis in the basal ganglia of the freely moving rat evidence has been obtained that neurotensin (NT) in threshold concentrations can counteract the D(2) agonist (intrastriatally perfused) induced inhibition of striatal dopamine (DA) release and of pallidal GABA release from the striato-pallidal GABA pathway, effects that are blocked by a NTR(1) antagonist SR48692. These results indicate the existence of antagonistic intramembrane NTR/D(2) receptor interactions in the striatal DA terminals and in the somato-dendritic regions of the striato-pallidal GABA neurons. By the NT-induced reduction of the D(2) mediated signals at the striatal pre- and postjunctional level DA transmission is switched towards a D(1) mediated transmission leading to increased activity in the striatopallidal and striatonigral GABA pathways. The former action will contribute to the motor inhibition and catalepsy found with NT treatment and underlies the use of NT receptor antagonists as a treatment strategy for Parkinson's disease. Nigral NT by an antagonistic NTR/D(2) receptor interaction in the DA cell body and dendrites may also increase nigral DA release leading to a D(2) mediated inhibition of the nigrothalamic GABA pathway. Such an effect, will instead result in antiparkinsonian actions. Thus, increases in NT transmission will have different consequences for the motor system depending upon where in the basal ganglia the increase takes place.

Actions at sites other than D 3 receptors mediate the effects of BP897 on l-DOPA-induced hyperactivity in monoamine-depleted rats

The role of D 3 receptors in the antiparkinsonian actions of l-DOPA and l-DOPA-induced dyskinesia (LID) remains unclear. The D 3 receptor partial agonist BP897 attenuates LID in primates without affecting the antiparkinsonian actions of l-DOPA, suggesting that “normalization” of D 3 activity is antidyskinetic [Bezard, E., Ferry, S., Mach, U., Stark, H., Leriche, L., Boraud, T., Gross, C., and Sokoloff, P., 2003. Attenuation of levodopa-induced dyskinesia by normalizing dopamine D 3 receptor function. Nat. Med. 9, 762–767]. However, subsequent studies have questioned these findings [Hsu, A., Togasaki, D.M., Bezard, E., Sokoloff, P., Langston, J.W., Di Monte, D.A., and Quik, M., 2004. Effect of the D 3 dopamine receptor partial agonist BP897 [ N-[4-(4-(2-methoxyphenyl)piperazinyl)butyl]-2-naphthamide] on l-3,4-dihydroxyphenylalanine-induced dyskinesias and parkinsonism in squirrel monkeys. J. Pharmacol. Exp. Ther. 311 , 770–777]. The D 3 receptor antagonist S33084 is not antidyskinetic yet enhances the antiparkinsonian actions of l-DOPA, suggesting that stimulation of D 3 receptors is not involved in LID. Here, we address the possibility that in vivo BP897 acts via mechanisms in addition to attenuation of D 3 signaling. l-DOPA (125 mg/kg) elicits hyperkinesia in reserpine-treated rats, the vertical component of which (rearing) is attenuated by agents with antidyskinetic actions in MPTP-lesioned primates and Parkinson's disease (PD) [Johnston, T.H., Lee, J., Gomez-Ramirez, J., Fox, S.H., and Brotchie, J.M., 2005. A simple rodent assay for the in vivo identification of agents with potential to reduce levodopa-induced dyskinesia in Parkinson’s disease. Exp. Neurol. 191 , 243–250]. BP897 (0.1, 0.3, 1.0 and 3 mg/kg) reduced l-DOPA-induced rearing by 0%, 44%, 86% and 57% respectively. In contrast, S33084 had no effect on l-DOPA-induced rearing (0.1 mg/kg, 115%; 0.3 mg/kg, 94%, 1 mg/kg, 134%; 3 mg/kg, 100%, of vehicle, all P > 0.05). Furthermore, S33084 failed to antagonize the effects of BP897 on l-DOPA-induced rearing. The influence of BP897 on l-DOPA-induced rearing was, however, mimicked by the selective D 2 antagonist L741,626. Finally, BP897 attenuated l-DOPA-induced horizontal activity, an action attenuated by S33084 and mimicked by L741,626. Thus, while BP897 may reduce LID, we raise the possibility that receptors other than D 3 receptors might be involved in this action.

Histamine H3 receptor agonists reduce L‐dopa–induced chorea, but not dystonia, in the MPTP‐lesioned nonhuman primate model of Parkinson's disease

L-dopa-induced dyskinesia (LID) remains a major complication of the treatment of Parkinson's disease. The neural mechanisms underlying LID are thought to involve overactivity of striatal glutamatergic neurotransmission, with resultant underactivation of the output regions of the basal ganglia. Histamine H3 heteroreceptors can reduce glutamate and gamma-aminobutyric acid (GABA) transmission in the striatum and substantia nigra reticulata, respectively. Thus, we tested whether the histamine H3 receptor agonists immepip and imetit can alleviate LID in the MPTP-lesioned marmoset model of Parkinson's disease. Coadministration of immepip (1 mg/kg) with L-dopa (15 mg/kg) was associated with significantly less total dyskinesia than L-dopa alone. When dyskinesia was separately rated as chorea and dystonia, coadministration of L-dopa with either immepip or imetit (both 10 mg/kg) significantly reduced chorea but had no effect on dystonia. The antidyskinetic actions of the H3 agonists were not accompanied by alteration of the antiparkinsonian actions of L-dopa. However, immepip (10 mg/kg), when administered as monotherapy, significantly increased parkinsonian disability compared to vehicle. Overall, the results obtained in this study suggest that histamine H3 receptors may be involved in the neural mechanisms underlying L-dopa-induced dyskinesia in Parkinson's disease.

The pharmacological effects of Salvia species on the central nervous system

Salvia is an important genus consisting of about 900 species in the family Lamiaceae. Some species of Salvia have been cultivated world wide for use in folk medicine and for culinary purposes. The dried root of Salvia miltiorrhiza, for example, has been used extensively for the treatment of coronary and cerebrovascular disease, sleep disorders, hepatitis, hepatocirrhosis, chronic renal failure, dysmenorrhea, amenorrhea, carbuncles and ulcers. S. officinalis, S. leriifolia, S. haematodes, S. triloba and S. divinorum are other species with important pharmacological effects. In this review, the pharmacological effects of Salvia species on the central nervous system will be reviewed. These include sedative and hypnotic, hallucinogenic, skeletal muscle relaxant, analgesic, memory enhancing, anticonvulsant, neuroprotective and antiparkinsonian activity, as well as the inhibition of ethanol and morphine withdrawal syndrome.

Lisuride, a Dopamine Receptor Agonist With 5-HT2B Receptor Antagonist Properties

The high incidence of fibrotic cardiac valvulopathies reported in association with the 8beta-ergoline dopamine (DA) agonist, pergolide, and also case reports for cabergoline and bromocriptine have made it necessary to review the theoretical basis and actual findings in the case of another DA agonist, the 8alpha-ergoline lisuride (used since the 1970s for migraine prophylaxis as well as since the 1980s for its prolactin-lowering and anti-Parkinson activity). We have reviewed the pharmacology of lisuride in relation to other DA agonists, and we have performed a throughout literature search as well as a search of our own and other adverse drug reaction databases for a possible relationship of lisuride with cardiac valvulopathy or for any reports of fibrosis in other locations. Our review of the pharmacology and the literature strongly suggests that drug-induced cardiac valvulopathies are always related to a stimulatory drug effect on trophic 5-HT(2B) receptors. As lisuride is devoid of such an effect, but on the contrary is an extremely potent 5-HT(2B) antagonist, an association of lisuride therapy with cardiac valvulopathies seems to be highly unlikely. In agreement with this hypothesis, not a single report of a cardiac valvulopathy associated with lisuride therapy has been identified in any database so far.Furthermore, against a background of an estimated 360,000 patient years, we have found only a very small number of cases of any other form of fibrosis (1x retroperitoneal, 2x pleural, 2x pulmonary, 1x interstitial pulmonary changes), in part combined with other risk factors and confounding variables. This closely matches 4 reports available from WHO (1x retroperitoneal, 3x pleural fibrosis). In addition, only 5 other possibly related conditions (3x pleural effusion, 1x pleuritis, 1x pericarditis) were identified in the lisuride adverse drug reaction database of Schering, Berlin. No link has been found between lisuride use and fibrotic cardiac valvulopathy, in agreement with the 5-HT(2B) receptor antagonist effect of this drug. The very low incidence of spontaneous reports of any other fibrosis could be even compatible with an association by chance in the population exposed to lisuride. Although close monitoring for this kind of side effects is still to be recommended in the therapy with lisuride, our data do not support the concept of a class effect suggesting that all ergot-derived drugs and especially DA receptor agonists with some chemical similarity to the ergot structure will cause or facilitate cardiac valvulopathies as observed with pergolide.

4‐Chloro‐2,2‐disubstituted Chromen‐3‐carboxaldehyde: Synthesis of some Fused Polycyclic Heterocycles as Anti‐inflammatory, Analgesic, Anticonvulsant, and Antiparkinsonian Agents

Some new aldazino 4, pyrazolo 5, thieno 8, and thiooxopyrimidino chromenes 10 were prepared via reaction of the corresponding beta-chlorocarboxaldehyde 3 with hydrazine hydrate, mercaptoacetic acid, and thiourea, respectively. Wherever, 4-chlorochromene derivatives 2 along with 4-chlorochromen-3-carboxaldehyde derivatives 3 were prepared from the corresponding ketone 1 with Vilsmeier-Haack reagent. Some of the new products showed good anti-inflammatory, analgesic, anticonvulsant, and antiparkinsonian activities comparable to indomethacin, diclofenace, carbamazepine, and benztropine.

Synthesis and Reactions of Some New Substituted Pyridine and Pyrimidine Derivatives as Analgesic Anticonvulsant and Antiparkinsonian Agents.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Improvement of cervico–trunco–brachial segmental dystonia with topiramate

Sirs: Topiramate (Topamax, Ortho-McNeil Pharmaceuticals, Raritan, NJ), a sulfamate-substituted monosaccharide, was approved in 1995 (1996 in the United States) for the treatment of epileptic disorders (including epileptic myoclonus [9]). Since then it was also approved for the prevention of migraine and its off label use has gained popularity as a weight reduction agent, in the treatment bipolar disorder [10], neuropathic pain [4] and in hyperkinetic movement disorders [3]. We report a patient with segmental cervicotrunco-brachial dystonia who experienced symptomatic benefit after treatment with topiramate. A 47-year-old ambidextrous male was initially evaluated in our Movement Disorders clinic (at the age of 40 years) for administration of botulinum toxin injections for his segmental dystonia which started about the age of 8 following a varicella-zoster viral infection. His dystonic symptoms involved the neck and shoulder muscles as well as the trunk and both upper extremities (left > right). His abnormal movements consisted of side-to-side trunk flexion associated with mild-moderate head tremors, shoulder elevation and action-induced upper limb dystonia of moderate intensity, mainly of the extensors of the wrist (left > right). The neck and shoulder dystonia has been highly responsive to botulinum toxin injections (usually about 300 units in both trapezius and splenius capitis and right sternocleidomastoid muscles) which had been given continuously since the age of 35 (every 4 months). The patient has also tried different combinations of lorazepam, clonazepam, propranolol, sodium valproate and baclofen with mild symptomatic benefit. He has a family history in which his sister has laryngeal dystonia and his father suffers from Parkinson’s disease. However, no genetic tests were performed. Neurological examination has consistently revealed trunk flexion movements associated with mild to moderate amplitude head tremors for the most part rotational with a tendency for the head to be mildmoderately rotated to the left, and a moderate left shoulder elevation. When he stretched out the upper extremities, there was mild dystonic posturing of both, left more than right. Sustained postural holding or task performance (writing, eating etc.) elicited dystonic activity of both upper extremities. EEG, brain MRI and copper studies were normal. The patient was gradually started on topiramate (up to 200 mg/day) at the age of 46 and experienced a marked improvement of his trunk and upper limb dystonic component, with marked reduction in trunk flexion and action-induced wrist extension. The patient did not report an improvement of his symptoms at lower doses of topiramate (100 mg–150 mg/day). However, about two months later he started complaining of a significant amount of eye pain associated with eye redness, blurred vision (which was diagnosed as angle closure glaucoma) as well as weight loss and occasional word-finding difficulty. After gradually discontinuing the topiramate all these symptoms (all known side-effects of topiramate [2, 8]) subsided. However, there was considerable deterioration of the dystonic features. There are limited data on the efficacy of topiramate on hyperkinetic movement disorders. It has been found to reduce symptoms of essential [3] and cerebellar tremor [11], and was reported to be effective in single cases of spinal myoclonus [14], Tourette’s syndrome [1] and vascular hemichorea/hemiballism [5]. Furthermore, topiramate has been reported to reduce levodopa-induced dyskinesia (without affecting the antiparkinsonian action of levodopa) in the MPTP-lesioned marmoset model of Parkinson’s disease (PD) [13]. The exact mechanism of action of topiramate in hyperkinetic movement disorders is unknown. It has been postulated that hyperkinetic disorders may be caused by decreased GABAergic transmission in the indirect basal ganglion pathway [7]. Consistent with that theory, it seems reasonable to believe that drugs that increase GABAergic neurotransmission would be beneficial. Topiramate has been proven to enhance GABA activity [12]. Topiramate has also AMPA receptor antagonistic properties [6]. Since overactive AMPA receptormediated transmission has been implicated in the development of hyperkinetic movement disorders (i. e. levodopa-induced dyskinesia) in animal models [13] it could provide a useful treatment for other hyperkinetic movement disorders like dystonia. In summary, there are reports (including the present one) that suggest the possible beneficial role of topiramate in the treatment of hyperkinetic movement disorders. However, one should always be aware of its potential side effects LETTER TO THE EDITORS

Synthesis and Reactions of Some New Substituted Pyridine and Pyrimidine Derivatives as Analgesic, Anticonvulsant and Antiparkinsonian Agents

A series of substituted pyridine and pyrimidine derivatives were synthesized as analgesic, anti convulsant, and antiparkinsonian agents by using compounds 1, 2, and 9 as starting materials. Pyr idino-imide derivative 3 was prepared by condensation of 1 with tetrachlorophthalic anhydride and compounds 4 and 5 were also obtained by reaction of compound 1 with 1,2,4,5-benzene-tetra carboxylic dianhydride and 1,4,5,8-naphthalenetetracarboxylic dianhydride, respectively. Similarly, compound 2 was reacted with previous anhydrides to afford the corresponding imide 6 and bis-imide derivatives 7 and 8, respectively. Bis-arylmethylene derivatives 9 were treated with hydrogen peroxide to afford the corresponding bis-oxiranocycloalkanone derivatives 10, which condensed with thiourea to give the corresponding thioxopyrimidine derivatives 11. Treatment of compound 11 with chloroacetic acid in the presence of anhydrous sodium acetate afforded the corresponding thiazolopyrim idine derivative 12 which condensed with aromatic aldehydes in acetic acid/acetic anhydride to give arylmethylene derivative 13. Also, compounds 13 could be prepared by reaction of compounds 11 with chloroacetic acid, aromatic aldehydes, and sodium acetate in a mixture of acetic acid and acetic anhydride. The pharmacological screening showed that many of these obtained compounds have good analgesic, anticonvulsant, and antiparkinsonian activities comparable to Valdecoxib, Carbamazepine, and Benzatropine as reference drugs.

Synthesis and biological activity of natural thiazoles: An important class of heterocyclic compounds

The class of heterocyclic compounds known as thiazole is found in many natural and synthetic products with a wide range of pharmacological activities, such as antiviral, anticancer, antibacterial, antifungal, anticonvulsant, antiparkinsonian and anti-inflammatory activities that can be well illustrated by the large number of drugs in the market containing this function group. Due to its importance, the aim of this review is to highlight the synthesis and biological activity of the thiazole natural products reported between 2000 and 2004.