Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0040822 (tremor)
 18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An insoluble graft copolymer consisting of the covalently bound polyoxyethylene to cross-linked polystyrene (HO-POE-PS) was prepared by anionic polymerization of ethylene oxide on the resin. The copolymer was then converted to the corresponding amino-polymer (H2N-POE-PS) and the latter was employed as the solid carrier for peptide synthesis. Although HO-POE-PS has successfully been employed as a carrier for peptide synthesis by the standard shaking procedure using t-butoxycarbonyl-amino acids, now we deemed it of interest to test its suitability for the continuous flow synthesis. Thus, the C-terminal octapeptide of the porcine insulin B chain (B23-30) was prepared by this procedure using a photolabile anchoring group and fluoren-9-ylmethoxycarbonyl-amino acids. All the reactions were carried out in a continuous flow manner in a steel column under pressure using a high-performance liquid chromatography (HPLC) system. At the end of the synthesis, a sample of the protected peptide was cleaved from the support by photolysis. For the cleavage of another sample, an aqueous solution of sodium carbonate was employed. The protected peptide was purified on silica gel and Sephadex-LH 20. All the protecting groups of a sample of the octapeptide were removed with piperidine/dimethylformamide and trifluoroacetic acid and the deblocked peptide was purified by ion-exchange chromatography. The free peptide was shown to be homogeneous by thin-layer chromatography, HPLC, and electrophoresis. The identify of the free octapeptide was confirmed by amino-acid analysis, 13C-nuclear magnetic resonance measurement and field-desorption mass spectrometry. The peptide was also shown to be free of racemization.
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PMID:Continuous flow peptide synthesis on aminopolyoxyethylene-polystyrene graft copolymer using Fmoc-strategy. 304 90

Beta-N-methylamino-L-alanine (BMAA) and beta-N-oxalylamino-L-alanine (BOAA) are chemically related amino acids present in the seeds of Cycas circinalis and Lathyrus sativus, respectively. Consumption of these seeds has been linked to Guam amyotrophic lateral sclerosis (BMAA) and lathyrism (BOAA; a form of primary lateral sclerosis). A single large dose of BOAA or BMAA causes seizures in newborn mice and postsynaptic neuronal edema and degeneration in CNS explants. We report that the acute neurotoxic actions of these amino acids are blocked selectively by specific glutamate-receptor antagonists (administered intracerebroventricularly) (i.c.v.) prior to the amino acid. Administration of BOAA i.c.v. to neonatal mice (ED100 = 50 micrograms) elicits a spectrum of time-dependent behavioral states including arm and leg rigidity, convulsions, and resting tremor. These are blocked in a dose-dependent manner by cis-2,3-piperidine dicarboxylic acid (PDA), an antagonist of quisqualate (QA)-preferring (A2) and kainate (KA)-preferring (A3) glutamate receptors (ED50s; 2.8 micrograms, rigidity; 1.4 micrograms, convulsions; 2.4 micrograms, resting tremor). BMAA induces a transitory hyperexcitable state followed by a long-lasting whole-body shake/wobble (ED100 = 1,000 micrograms, i.c.v.). These responses are antagonized selectively and dose-dependently by 2-amino-7-phosphonoheptanoic acid (AP7), an N-methyl-D-aspartate (NMDA) or A1 glutamate-receptor antagonist (ED50 = 0.45 microgram). Taken collectively, our data indicate that the acute neuronotoxic actions of BOAA and BMAA (or a metabolite) operate through different glutamate-receptor species. BMAA likely exerts most of its action indirectly via the A1 glutamate receptor, while BOAA acts principally at the A2 and/or A3 receptor.
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PMID:Specific antagonism of behavioral action of "uncommon" amino acids linked to motor-system diseases. 314 80

A neurologic deficit characterized by hypokinesia, postural flexion, and to a lesser extent, rigidity, tremor and myoclonus, has been observed in cynomolgus monkeys following administration of 1-methyl-4-(1-methylpyrrol-2-yl)-4-piperidinol (MMPP), a novel 4-substituted piperidine. The syndrome, similar to that described for 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), developed within 3-7 days after oral or i.v. dosing, and was accompanied by lesions in the substantia nigra. The behavioral syndrome was seen to a lesser extent in dogs but not in rats. MMPP contains a hydroxyl group on the 4-position of the pyridine ring; the corresponding dehydration product was inactive.
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PMID:A Parkinson-like neurologic deficit in primates is caused by a novel 4-substituted piperidine. 369 24

The onset pressures for the tremor, myoclonus and convulsions seen in the high pressure neurological syndrome (HPNS) are increased following cis-2,3-piperidine dicarboxylic acid 1 mmol/kg in the rat. Glutamic acid diethyl ester 1-3 mmol/kg has no effect on tremor or myoclonus, but increases the convulsion pressure when 3 mmol/kg is given immediately before compression. These and earlier data with 2-amino-7-phosphonoheptanoic acid suggest that excitation at the N-methyl-D-aspartate receptor is important in HPNS tremor, and that excitation at the quisqualate receptor contributes to HPNS convulsions.
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PMID:Effect of excitatory amino acid antagonists on the high pressure neurological syndrome in rats. 609 58

The excitatory amino acid analogues kainate, quisqualate, domoic acid, 4-fluoroglutamate, homocysteic acid and N-methylaspartate as well as the tremor-inducing drugs harmaline and oxotremorine all induced significant elevations in cyclic guanosine monophosphate (cGMP) levels in the cerebellum in vivo. The putative antagonists of excitatory amino acids, 2-amino-5-phosphonovalerate (APV) and piperidine dicarboxylate (PDA) both blocked the actions of the tremorogens. Piperidine dicarboxylate also blocked the in vivo activity of all the amino acid analogues except homocysteic acid and N-methylaspartate. 2-Amino-5-phosphonovalerate (APV) was inactive against kainate, quisqualate and homocysteic acid. It therefore appears that PDA and APV are useful tools for the further study of the function of glutamate and asparatate receptors.
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PMID:Antagonists of excitatory amino acids and cyclic guanosine monophosphate in cerebellum. 613 Apr 88

The lipophilic t-butyl analog of 1-alkyl-4,4-diphenyl piperidine, budipine, possesses a polyvalent spectrum of mechanisms of action. Budipine experimentally increased the brain content of norepinephrine, serotonine, dopamine and histamine in reserpine treated rats. Budipine did not alter the receptor affinity of these neurotransmitters but antagonizes the effect of NMDA at its receptor binding site in vitro. Budipine reduced MPP+ toxicity in the nigrostriatal system of mice. This complex pharmacologic profile is not comparable to the one of convenient antiparkinsonian drugs. In clinical trials budipine reduced tremor, akinesia and rigidity. Budipine induced a relevant additional positive effect in patients with an optimal dopaminergic therapy based on levodopa and dopamine agonists, such as bromocriptine. Current available data suggest that the need for levodopa application in early stages of the disease may be postponed by budipine and that the long-term application of budipine may induce a levodopa-sparing effect.
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PMID:Clinical efficacy of budipine in Parkinson's disease. 1037 Sep 3

The discovery of a novel series of potent and selective T-type calcium channel antagonists is reported. Initial optimization of high-throughput screening leads afforded a 1,4-substituted piperidine amide 6 with good potency and limited selectivity over hERG and L-type channels and other off-target activities. Further SAR on reducing the basicity of the piperidine and introducing polarity led to the discovery of 3-axial fluoropiperidine 30 with a significantly improved selectivity profile. Compound 30 showed good oral bioavailability and brain penetration across species. In a rat genetic model of absence epilepsy, compound 30 demonstrated a robust reduction in the number and duration of seizures at 33 nM plasma concentration, with no cardiovascular effects at up to 5.6 microM. Compound 30 also showed good efficacy in rodent models of essential tremor and Parkinson's disease. Compound 30 thus demonstrates a wide margin between CNS and peripheral effects and is a useful tool for probing the effects of T-type calcium channel inhibition.
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PMID:Discovery of 1,4-substituted piperidines as potent and selective inhibitors of T-type calcium channels. 1881 68

We recently demonstrated that aspartoacylase (Aspa) and hyperpolarization-activated cyclic nucleotide-gated potassium channel 1 (Hcn1) genes were causative of essential tremor (ET) in rats. This finding was obtained using Aspaem34Kyo/Hcn1A354V double-mutant rats, but they were bred on a heterogeneous genetic background of two strains, F344 and WTC. Here, we developed an Aspaem34Kyo/Hcn1em1Kyo double-knockout rat strain with a homogenous F344 genetic background and studied the ability of glutamate receptor antagonists to suppress ET. The F344-Aspa/Hcn1 double-knockout rats exhibited spontaneous, intense body tremor equivalent to that in the double-mutant rats. N-acetyl-aspartate (NAA), a substrate of ASPA, showed accumulation in all brain regions and in the spinal cord. However, N-acetyl-aspartyl-glutamate (NAAG), which is derived from NAA and interacts with glutamatergic receptors, was decreased in the medulla oblongata of the double-knockout rats. The tremor was suppressed by 3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-1-phosphonic acid, an N-methyl-D-aspartate (NMDA) receptor antagonist, in F344-Aspa/Hcn1 double-knockout rats. The non-NMDA glutamate receptor antagonist NBQX weakly inhibited the tremor, while the metabotropic glutamate receptor antagonist LY341495 showed no effect. In addition, both NR2B subunit-specific (Ro 25-6981) and NR2C/NR2D subunit-specific (cis-piperidine dicarboxylic acid) NMDA receptor antagonists suppressed the tremor. These data indicated that the pathogenesis of tremor in Aspa/Hcn1 double-knockout rats involved ionotropic glutamate receptors, particularly NMDA receptors.
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PMID:Involvement of NMDA receptors in tremor expression in Aspa/Hcn1 double-knockout rats. 3250 87