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)

GEA 857 [2-(4-chlorophenyl)-1,1-dimethylethyl 2-amino-3-methylbutanoate], a structural analogue of the 5-HT uptake blocker alaproclate, was tested for its ability to modify tremor and salivation induced by muscarinic agonists (oxotremorine, arecoline) and acetylcholinesterase inhibitors (physostigmine, THA) in the male rat. These agents were employed at submaximal doses. GEA 857, similarly to alaproclate (Ogren et al. 1985a & b), produced a dose-dependent, statistically significant (in the 5-20 mg/kg dose range) enhancement of the tremor response induced by all four cholinergic stimulants. However, unlike alaproclate, GEA 857 failed to enhance salivation in a consistent manner. GEA 857 itself did not produce tremor in the absence of the muscarinic agonists or the acetylcholinesterase inhibitors. The potentiation of oxotremorine tremor by GEA 857 could be fully blocked by atropine (1 mg/kg intraperitoneally). Unlike alaproclate, GEA 857 failed to affect 5-HT uptake or 5-HT metabolism in the 10-20 mg/kg dose range. However, similarly to the action of alaproclate, the potentiating effect of GEA 857 on muscarinic responses could be explained neither by actions on serotonergic mechanisms nor by actions on muscarinic receptor mechanisms in the striatum. Evidence is presented suggesting that the ability of GEA 857 to enhance responses evoked by muscarinic agonists involves inhibitory properties of GEA 857 at certain membranal Ca(2+)-dependent K+ channels, the blockade of which can potentiate or prolong muscarinic cholinergic actions.
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PMID:GEA 857, a putative blocker of potassium conductance, enhances muscarinic agonist-evoked responses: dissociation from an action on 5-HT mechanisms. 143 27

The ability of some beta-adrenoceptor agonists to induce tremor via skeletal muscle beta 2-adrenoceptors in conscious unrestrained rats has been investigated. Tremor was assessed by visual observation and by an objective method based on accelerometry. Infusion of isoprenaline or terbutaline did not cause tremor, neither did beta-stimulation potentiate an established mild tremor produced by central muscarinic receptor stimulation. Since beta-agonists readily produce tremor in man via skeletal muscle beta 2-adrenoceptor stimulation, our findings indicate that these receptors have a different function in the rat.
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PMID:Beta-adrenoceptor agonists do not cause tremor in the conscious rat. 286 14

Choice of an antidepressant medication is, in part, based on the side effects produced by a drug and the desire to avoid certain reactions in a particular patient. The clinician needs a reliable method of predicting which medications are most likely to produce specific untoward effects. Understanding the synaptic pharmacology of the most commonly used agents could serve as a tool for predicting possible side effects and drug-drug interactions. Antidepressant drugs alter neurotransmitter effects at nerve synapses, probably by blocking norepinephrine and serotonin reuptake, and blockade of neurotransmitter receptor sites - primarily the histamine H1 receptor, the muscarinic receptor, and the alpha-1-adrenoceptor. Possible clinical side effects related to some of these interactions include tachycardia, tremor, and (possibly) male sexual dysfunction (associated with norepinephrine reuptake blockade); sedation (associated with histamine H1 blockade); orthostatic hypotension, dizziness, and reflex tachycardia (associated with alpha-1-adrenoceptor blockade), and blurred vision, dry mouth, and memory dysfunction (associated with muscarinic receptor blockade). Pharmacologic data that demonstrate the potencies and selectivities of the antidepressant drugs for reuptake blockade and receptor site antagonism might allow the clinician to make an informed, rational choice of antidepressant therapy. This paper presents data on drug potencies and selectivities, and attempts to relate these data to anticipated side effects and drug-drug interactions.
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PMID:Pharmacology of antidepressants. 289 25

The enantiomers of three 5-methyl-2-pyrrolidone analogues of the muscarinic agent oxotremorine (1) were synthesized. The pyrrolidine derivative (R)-13 was an antagonist to carbachol in the guinea pig ileum and also showed central and peripheral antimuscarinic activity in vivo. It was more potent and more selective than atropine in antagonizing the central effects of 1. The dimethylamino analogue (R)-14 and the trimethylammonium salt (R)-15 were potent agonists in the guinea pig ileum. (R)-14 showed both central muscarinic (hypothermia) and central antimuscarinic activity (antagonism of oxotremorine-induced tremor) in vivo. The R enantiomers of 13-15 were considerably more potent than the S enantiomers in vivo and in vitro irrespective of whether agonist or antagonist activity was measured. From a comparison of the contribution of the methyl group at the chiral center to the overall affinities, it is suggested that agonists and antagonists in this series bind in an essentially identical manner to the muscarinic receptor.
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PMID:Stereoselectivity of muscarinic receptors in vivo and in vitro for oxotremorine analogues. N-[4-(tertiary amino)-2-butynyl]-5-methyl-2-pyrrolidones. 293 18

Rolipram, in contrast to the tricyclic antidepressants amitriptyline and imipramine or the acetylcholine receptor antagonist atropine, failed to antagonize the salivation, hypothermia, or tremor caused in mice by the muscarinic receptor agonists pilocarpine or oxotremorine. The absence of anticholinergic activity, the extremely low therapeutic dose, and the novel mechanism of antidepressant action suggest that rolipram may also be a well tolerable antidepressant suitable for the treatment of problematic subpopulations of depressives such as elderly patients.
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PMID:Absence of anticholinergic activity of rolipram, an antidepressant with a novel mechanism of action, in three different animal models in vivo. 322 52

The present study sought to assess whether the compound N-[4-(2-chloro-ethylmethylamine)-2-butynyl]-2-pyrrolidone (BM123), a potent muscarinic agonist that binds irreversibly to the muscarinic receptor (mAChR), has long-lasting functional effects which may be related to a reduction in functional mAChRs. Passive (inhibitory) avoidance performance, one-way active avoidance learning, and spontaneous alternation behavior were studied in rats. The results confirmed the acute muscarinic stimulating effects of BM123, including tremor, salivation, chromodacryorrhea and hypothermia. In addition, when measured 3-4 days after administration, rats treated with BM123 had disrupted spontaneous alternation performance and tended to have impaired performance for the inhibitory avoidance task with facilitated acquisition of active avoidance. This spectrum of effects is consistent with previous reports showing a 20-40% reduction in mAChRs at these times after BM123. The reversible muscarinic agonist, oxotremorine, was without significant effect. In a further experiment, it was found that pretreatment with methyl atropine did not prevent the disruption of spontaneous alternation behavior by BM123, whereas pretreatment with atropine did. Thus, these long-lasting behavioral effects of BM123 are related to its alkylation of and subsequent reduction in central mAChRs.
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PMID:Effects of an irreversible muscarinic agonist (BM123) on avoidance and spontaneous alternation performance. 324 11

Studies of muscarinic receptor concentration and comparative binding assays of agonists and antagonists are presently done in vitro by incubation and measurement of the binding to tissue homogenates of the radiolabelled potent antagonists 3H-scopolamine or 3H-quinuclidinyl benzilate. We have developed a technique based on gas chromatography-mass spectrometry that allows studies of the muscarinic receptor concentration to be performed in vivo under physiologic conditions. By injecting the optical antipodes of atropine, D- and L-hyoscyamine separately in mice and following their kinetics in different parts of the brain it was possible to separate the specific receptor binding of the active antipode L-hyoscyamine from that of the inactive antipode D-hyoscyamine, representing unspecific binding. Two hrs after the administration of L-hyoscyamine, 2 mg/kg intravenously, its concentration in brain was found to represent "maximum" specific binding. The physiological significance of specifically bound L-hyoscyamine was tested on its blocking effect on oxotremorine induced tremor.
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PMID:A method using L-hyoscyamine for the study of muscarinic acetylcholine receptor binding in vivo. 356 91

Diazepam has previously been shown to affect the acetylcholine synthesizing system in mouse brain. This paper reports studies on the effect of diazepam on muscarinic receptor density and on pharmacological effects of oxotremorine. The receptor density was studied using a new technique that allows such studies to be performed in vivo under physiological conditions. The method is based on the fact that L-hyoscyamine, the active antipode of atropine, binds specifically to muscarinic receptors in the brain, and can be measured with high sensitivity by gas chromatography--mass spectrometry. Diazepam was found to modify the binding properties of muscarinic receptors in CNS, thereby decreasing the functional receptor pool. It also prevented tremor induced by the muscarinic agonist oxotremorine. Diazepam could however not prevent the hypothermia induced, but rather accentuated this effect of oxotremorine. It is concluded that diazepam, directly or indirectly, influences the effect of cholinergic stimulators by modulating the size of the muscarinic receptor pool.
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PMID:Effects of diazepam on muscarinic acetylcholine receptor binding in vivo and on oxotremorine-induced tremor and hypothermia in mice. 358 23

The effects of the compound RS 86 (2-ethyl-8-methyl-2,8-diazaspiro-[4,5]-decan-1,3-dion hydrobromide) in a number of in vitro and in vivo test systems for muscarinic cholinergic activity were analyzed and compared to those of classical muscarinic receptor agonists. In radioligand binding assays RS 86 presented high nanomolar apparent affinity only for sites labeled by 3H-muscarinic receptor agonists while its apparent affinity for sites labeled by 3H-muscarinic receptor antagonists including [3H]QNB, [3H]NMS and [3H]pirenzepine was in the micromolar range. RS 86 had no or only low affinity (IC50 greater than 10 microM) for other neurotransmitter or drug receptor sites. The compound induced scopolamine-sensitive contractions of the isolated guinea-pig ileum showing a pD2 of 6 in this model. In the isolated rat superior cervical ganglion RS 86 was also an agonist with a pD2 of 6.7. When given to mice or rats by different routes RS 86 induced central and peripheral effects typical of a muscarinic receptor agonist, such as hypothermia, tremor, mydriasis, salivation, lacrimation, diarrhoea and modification of behavior as observed in an open field. In several of these tests RS 86 was about 10 times less potent than oxotremorine but more potent than arecoline, pilocarpine, aceclidine or the compound (cis) AF-30. The ED50 values for some central effects, including the induction of hypothermia and alert non-mobile behavior were lower than those for tremor and peripheral effects. Some of the effects lasted for up to 6 h, depending on the dose. Finally, RS 86 administration resulted in modifications of brain acetylcholine turnover and high affinity choline uptake typical of a central muscarinic receptor agonist. Taken together these results demonstrate clearly that RS 86 is a potent, centrally acting, selective muscarinic receptor agonist. RS 86 appears to be an adequate tool for the clinical examination of the cholinergic hypothesis of Alzheimer's disease.
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PMID:The pharmacological assessment of RS 86 (2-ethyl-8-methyl-2,8-diazaspiro-[4,5]-decan-1,3-dion hydrobromide). A potent, specific muscarinic acetylcholine receptor agonist. 373 91

In an attempt to elucidate the mechanism of wet dog shakes (WDS) produced by carbachol administered into the rat lateral brain ventricle, the effects of blockade of muscarinic and nicotinic receptors on shaking response and the effects of carbachol on central catecholaminergic, serotonergic (5-HT) and GABAergic functions were studied in rats. The muscarinic receptor antagonists, atropine and scopolamine attenuated WDS produced by carbachol, whilst a peripherally active muscarinic receptor antagonist, scopolamine methyl nitrate, failed to influence WDS. The nicotine antagonist, mecamylamine, did not affect WDS caused by carbachol either. Carbachol dose dependently decreased brain concentration of noradrenaline (NA) but failed to affect the concentration of dopamine (DA). While the brain concentration of 5-HT was unchanged, the concentration of 5-hydroxyindoleacetic acid (5-HIAA) was increased in a dose-related manner. The catecholamine turnover times were unaffected whereas 5-HT turnover time was significantly prolonged. Atropine, but not mecamylamine, prevented the decrease in brain NA induced by carbachol. Consequently, the carbachol-induced enhancement in the level of 5-HIAA was completely blocked by atropine and only slightly influenced by mecamylamine. Neither brain GABA concentration nor glutamic acid decarboxylase activity were affected by carbachol. Behavioral and biochemical data suggest that WDS produced by carbachol may be mediated through the stimulation of central muscarinic receptors. The anatomical localization and exact mechanism of carbachol-induced WDS remain to be elucidated.
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PMID:Studies on the mechanism of wet dog shakes produced by carbachol in rats. 620 Aug 91


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