Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.1.8 (cholinesterase)
12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of hemicholinium-3 (HC-3) on responses of the rat isolated bladder and ileum to acetylcholine and carbachol was investigated in the absence and presence of a number of anticholinesterases. Responses of the bladder to acetylcholine were potentiated by DFP, edrophonium, BW284C51 and physostigmine but were unaffected by the specific butyrylcholinesterase inhibitor iso-OMPA. Responses to carbachol were not potentiated by the anticholinesterases. HC-3 (1.7 X 10(-4) M) inhibited responses to carbachol without affecting those to acetylcholine. In the presence of physostigmine or DFP responses to acetylcholine were inhibited by HC-3 but no such inhibition was observed in the presence of BW284C51, edrophonium or iso-OMPA or a combination of the latter two anticholinesterases. Responses to carbachol were also inhibited to a greater extent in the presence of DFP. In the ileum, responses to acetylcholine were increased in the presence of DFP, edrophonium and physostigmine but were unaffected by iso-Ompa. responses to carbachol were not increased by any of the anticholinesterases. HC-3 (2.8 X 10(-4) M) inhibited responses to both acetylcholine and carbachol in the ileum and the degree of inhibition was not significantly altered by the presence of any of the anticholinesterases used. Although a weak anticholinesterase, HC-3 was also found to decrease the inhibitory action of physostigmine on the hydrolysis of acetylcholine by homogenates of rat ileum. A similar effect was noted with DFP but not with edrophonium. The results obtained do not support a prejunctional action for HC-3 in antagonizing responses to carbachol. It is concluded that in addition to an inhibitory action on the post-junctional muscarinic receptor HC-3 may interfere with the anticholinesterase activity of some cholinesterase inhibitors such as physostigmine and DFP but not edrophonium.
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PMID:The effect of cholinesterase inhibitors on the antimuscarinic effect of hemicholinium-3 (HC-3) in the rat. 0 55

Phencylidine derivatives exhibit multiple interactions with cholinergic systems: they block nicotinic and muscarinic receptors,and inhibit both acetyl and butyrylcholinesterase. In peripheral tissue, the net pharmacological effects of the phencyclidines is antiacetylcholine activity. The dissociation constants measured in isolated smooth muscle and from competition experiments for the muscarinic high-affinity binding sites in brain homogenates (Kd = 10(-5) - 10(-6) M) are 3--4 orders of magnitude lower than those of anticholinergic glycolate esters. However, phencyclidines have comparable potency to that of d-tubocurarine in blocking the nicotinic receptor in the isolated frog rectus abdominis (Kd = 10(-6) M). Brain uptake experiments of (3H) labeled phencyclidine showed that during the time period in which central effects are observed with these drugs their concentration in brain reaches values close to the Kd (10(-5) - 10(-6) M). This finding, and the cross tolerance observed in vivo between phencyclidine and other centrally acting cholinergic drugs supports the possible involvement of cholinergic interactions in the psychotropic action of phenyclidine derivatives. Quantum chemical calculations of the interaction pharmacophores of drugs in the phencyclidine series have indicated the molecular determinants for the interaction of these drugs with the muscarinic receptor. The calculations revealed that these drugs can match the reactivity characteristics of ACh and the semi-rigid muscarinic agonist 3-acetoxyquinuclidine, but their rigid molecular frame will be conductive to antagonistic rather than agonistic activity when the drug-receptor complex is formed. The identification of a "cholinergic interaction pharmacophore" for these drugs by quantum mechanical calculations made possible the suggestion of other active phencyclidine derivatives, e.g. p-NH2 and p-OH analogs which proved to be equipotent to phencyclidine. The inactivity of the p-NO2 derivative was also predicted on this basis and served as an additional confirmation of the theoretical criterion for activity; the difference between the activities of the ethynyl and cyano derivatives was explained by the modification of the cholinergic interaction pharmacophore. On the basis of these theoretical predictions, electrophysiological studies were carried out by the others and the results prompted the suggestion that "physostigmine is of potential value in the treatment of post-operative patients emerging from ketamine anesthesia and in the treatment of phencyclidine overdosed patients".
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PMID:Some structure activity relationships of phencyclidine derivatives as anticholinergic agents in vitro and in vivo. 42 35

The antiacetylcholine and anticholinesterase potencies of four 1-phenylcyclohexylamine derivatives were estimated by measuring their antagonism to the contractile response of smooth and striated muscles and their inhibition of cholinesterase activity. In addition, their affinities towards the central muscarinic receptor from mouse brain homogenate were determined by competition experiments in vitro. Relative to atropine, these drugs exerted mild antimuscarinic activity in both isolated smooth muscle and in the competition experiments. On the other hand, they were found to exert antinicotinic potencies equal to that of d-tubocurarine in the striated muscle. The concentration of (3H)-phencyclidine taken up by mouse brain in vivo could be correlated with its dissociation constants from the central muscarinic binding sites, as well as with the Ki values for acetylcholinesterase inhibition, both determined in vitro. Since these drugs have a similar rigid spatial molecular structure, it is proposed that the variations in the potency of their cholinergic interactions stemmed mainly from the structural changes in the region of the 'cationic head'.
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PMID:Anticholinesterase and antiacetylcholine activity of 1-phenylcyclohexylamine derivatives. 92 35

The effect of the muscarinic receptor antagonist AF-DX 116 on the inhibitory action of muscarinic agonists and on responses mediated by nicotinic or muscarinic ganglionic transmission was studied in the superior cervical ganglion of the anesthetized cat. The postganglionic compound action potential evoked by cervical sympathetic trunk stimulation was depressed by methacholine or acetylcholine (ACh) injected into the ganglionic arterial supply. The depression was blocked by AF-DX 116. The compound action potentials evoked by preganglionic stimulus trains were also depressed when the intratrain frequency was 2 Hz or greater. This intratrain depression was, however, insensitive to AF-DX 116. The anticholinesterase drug physostigmine markedly enhanced the intratrain depression of the compound action potential. This effect was reversed by AF-DX 116. During nicotinic receptor block with hexamethonium, preganglionic stimulus trains with intratrain frequencies of 5 Hz or greater produced nicitating membrane contractions that could be blocked by the M1 muscarinic receptor antagonist pirenzepine. The amplitude of the contractions increased with frequency and reached a maximum at 20-40 Hz. AF-DX 116 had no effect on these responses. After administration of physostigmine, the amplitude of the nictitating membrane responses decreased with increasing intratrain frequency. AF-DX 116 reversed this effect. The data suggest that, in the superior cervical ganglion, AF-DX 116 sensitive muscarinic receptors which depress synaptic transmission are activated by exogenous agonists but not by the ACh released by the preganglionic axon terminals unless cholinesterase activity is inhibited.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:An AF-DX 116 sensitive inhibitory mechanism modulates nicotinic and muscarinic transmission in cat superior cervical ganglion in the presence of anticholinesterase. 133 12

A single dose of the organophosphate insecticide O,O'-diethyl-O-3,5,6- trichloro-2-pyridylphosphorothioate [chlorpyrifos (CPF), 279 mg/kg, SC] caused extensive inhibition of cortical and striatal cholinesterase (ChE) activity in adult rats at 2 (94-96%), 4 (82-83%), and 6 (58-60%) weeks after treatment. These persistent changes in ChE activity were concomitant with reductions in muscarinic receptor binding sites in cortex (34, 33, and 18% reduction in Bmax) and striatum (48, 40, and 23% reduction in Bmax) at 2, 4, and 6 weeks after exposure. Neither ChE activities nor muscarinic receptor densities were different from control levels at 12 weeks after exposure. CPF treatment caused a reduction in locomotor activity for the first 2 days after treatment, after which basal activity levels were not different from controls. CPF-treated rats showed higher activity relative to controls, however, following challenge with scopolamine (1 mg/kg, IP) at 2, 4, 6, 8, and 12 weeks after treatment. These data indicate that acute exposure to CPF in adult rats can cause long-term neurobehavioral changes that may persist following the recovery of neurochemical parameters associated with exposure and tolerance to cholinesterase inhibitors.
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PMID:Long-term neurochemical and behavioral effects induced by acute chlorpyrifos treatment. 137 35

The effects of muscarinic receptor antagonists on ACh release were studied in the absence or presence of cholinesterase (ChE) inhibition using the isolated perfused chicken heart. Presynaptic inhibitory muscarinic autoreceptor were characterized by determining the potency of various antagonists to enhance [3H]-ACh release evoked by field stimulation (3 Hz, 1 min). The order of potencies was: (+/-)-telenzepine > atropine > 4-DAMP > silahexocyclium > pirenzepine > hexahydro-siladifenid-ol > AF-DX 116. The comparison with known pA2 values for M1-, M2- and M3-receptors revealed that the presynaptic autoreceptor meets the criteria of an M1-receptor. Basal, not electrically evoked overflow of unlabelled ACh into the perfusate was caused by 'leakage' release (non-exocytotic), as it was independent of extracellular Ca2+. Muscarinic receptor antagonists failed to enhance basel overflow. In contrast, when ChE activity was inhibited by 10(-6) M tacrine or pretreatment with 10(-4) M DFP, the ACh overflow was partially Ca(2+)-dependent and was reduced by tetrodotoxine. Moreover, block of the inhibitory muscarinic autoreceptors by (+/-)-telenzepine or pirenzepine caused a several-fold enhancement of the ACh release. The potencies of these antagonists were identical to those found for the electrically evoked [3H]-ACh release. The rate of ACh release enhanced by ChE inhibition plus telenzepine corresponds to about 12% of the total ACh pool per min, which is about the maximum amount of ACh that is available for any kind of stimuli. The release was dependent on the presence of exogenous choline. Hence elevation of ACh release led to a correspondingly enhanced ACh synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibitory and excitatory muscarinic receptors modulating the release of acetylcholine from the postganglionic parasympathetic neuron of the chicken heart. 143 22

In order to clarify the role of the amygdala in the working and reference memory of rats in the three-panel runway task, the effects of lesions of subnuclei of the amygdaloid complex on this behavior were studied. Rats that had been trained preoperatively, until they achieved the criterion of learning, were subjected to lesions of the amygdala. In the working memory task, lesions of the basolateral subdivision of the amygdala caused a significant increase in the number of errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points), while lesions of the corticomedial amygdala had no effect on working memory errors. The increase in working errors, observed in basolateral amygdaloid-lesioned rats, declined gradually as retraining sessions were given once each day, reverting to control levels on and after the sixth session. In the reference memory task, the number of errors was not affected by lesions of the basolateral or corticomedial amygdala. The increase in working memory errors, induced by lesions of the basolateral amygdala was significantly reduced by intraperitoneal administration of the inhibitors of cholinesterase, tetrahydroaminoacridine (0.32-1.0 mg/kg) and physostigmine (0.032-0.1 mg/kg), and the muscarinic receptor agonist, oxotremorine (0.1 mg/kg), before the runway test. These findings suggest that the basolateral amygdala is selectively involved in working memory but not in reference memory and that the lowering of central cholinergic function may account for the impairment of working memory, induced by lesions of the basolateral amygdala.
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PMID:Involvement of cholinergic mechanisms in impairment of working memory in rats following basolateral amygdaloid lesions. 143 98

The binding of [3H] quinuclidinyl benzilate (QNB) to rat striatum membranes after diisopropylfluorophosphate (DFP) induced seizures was characterized. There was a 36% decrease in Kd and a 33% decrease in the number of muscarinic receptors. Paraoxon caused inhibition fo [3H] QNB binding to the striatal membranes of intact rats. It is possible that a direct action of DFP on the muscarinic receptor is not the cause of anti-cholinesterase-induced changes in [3H] QNB binding.
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PMID:[Effects of diisopropylfluorophosphate, paraoxon and dichlophos on [3H] quinuclidinyl benzylate binding to the rat striatum synaptic membranes]. 147 63

The present study examined the role of spinal cholinergic modulation of spinal mechanical and thermal transmission. Intrathecal administration of the cholinergic muscarinic receptor antagonists atropine or scopolamine in awake rats produced a dose-dependent decrease in the nociceptive mechanical withdrawal threshold of the rat tail. Pirenzepine, a selective muscarinic receptor type 1 antagonist, produced a similar effect at greater doses while mecamylamine, a nicotinic receptor antagonist, was without effect. The nociceptive tail flick (TF) reflex evoked by noxious heating was unaffected by the above drugs. Intrathecal administration of the cholinesterase inhibitor physostigmine produced a rapid, reversible and significant increase in the mechanical withdrawal threshold; TF latency was increased slightly but not significantly. Intrathecal administration of morphine, carbachol or clonidine all produced dose-dependent increases in TF latency; morphine and carbachol, but not clonidine, also increased the mechanical withdrawal threshold significantly. Intrathecal pretreatment with atropine reversed carbachol-produced increases in TF latency and the mechanical withdrawal threshold but did not affect increases in TF latency produced by intrathecal morphine or clonidine. The morphine-produced increase in the mechanical withdrawal threshold, however, was shifted rightward in a parallel fashion by intrathecal pretreatment with atropine. Intrathecal pretreatment with yohimbine did not affect the inhibitory effect of carbachol on either TF latency or the mechanical withdrawal threshold. These results suggest that a tonic, endogenous cholinergic muscarinic influence in the spinal cord, independent of spinal adrenergic mechanisms, modulates spinal mechanical transmission.
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PMID:Tonic cholinergic inhibition of spinal mechanical transmission. 166 Oct

Muscarinic receptor stimulation or depolarization with elevated extracellular K+ induced rapid and sustained increases in mass accumulations of myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] and myo-inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P4] in cerebral cortex slices. Synergistic but transient responses of both inositol polyphosphate second messengers were observed when slices were stimulated with carbachol under depolarizing conditions; this synergy was observed as an increase in the maximal responsiveness, with no significant change in EC50 values for carbachol. Omission of buffer Ca2+ ([Ca2+]e 10-20 microM) reduced basal Ins(1,4,5)P3 and Ins(1,3,4,5)P4 concentrations; the relative stimulatory effects of muscarinic receptor stimulation were maintained, but the effects of depolarization were markedly attenuated under these conditions. A component of the response to depolarization appeared to be indirectly mediated by the release of acetylcholine, because the K(+)-evoked increase in Ins(1,3,4,5)P4 was enhanced by the cholinesterase inhibitor physostigmine, and was partially attenuated by atropine. An additive suppression by nitrendipine suggests that entry of Ca2+ through L-type Ca2+ channels may serve to accelerate phosphorylation of Ins(1,4,5)P3 by 3-kinase. Norepinephrine did not significantly increase Ins(1,4,5)P3 or Ins(1,3,4,5)P4 accumulation; however, in the presence of depolarizing K+, norepinephrine caused a dramatic increase in Ins(1,3,4,5)P4 mass accumulation. In contrast, the excitatory amino acid quisqualate caused significant increases in the mass accumulations of both inositol polyphosphates measured, with no further increase being observed under depolarizing conditions. The results are discussed with respect to the interactive effects of agonist and depolarization stimuli on inositol polyphosphate accumulation which might more accurately reflect the conditions pertaining in vivo.
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PMID:Depolarization and agonist-stimulated changes in inositol 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate mass accumulation in rat cerebral cortex. 186 Nov 43


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