- The E loop of the transmitter-binding site is a key determinant of the modulatory effects of physostigmine on neuronal nicotinic α4β2 receptors. [Journal Article]
- MPMol Pharmacol 2016 Nov 28
- Physostigmine is a well-known inhibitor of acetylcholinesterase, which can also activate, potentiate and inhibit acetylcholine receptors, including neuronal nicotinic receptors comprising α4 and β2 s...
Physostigmine is a well-known inhibitor of acetylcholinesterase, which can also activate, potentiate and inhibit acetylcholine receptors, including neuronal nicotinic receptors comprising α4 and β2 subunits. We have found that the two stoichiometric forms of this receptor differ in the effects of physostigmine. The form containing 3 copies of α4 and 2 of β2 was potentiated at low concentrations of ACh and physostigmine, while the form containing 2 copies of α4 and 3 of β2 was inhibited. Chimeric constructs of subunits indicated that the presence of inhibition or potentiation depended on the source of the extracellular ligand-binding domain of the subunit. Further sets of chimeric constructs demonstrated that a portion of the ACh-binding domain, the E loop, is a key determinant. Transferring the E loop from the β2 subunit to the α4 subunit resulted in strong inhibition, while the reciprocal transfer reduced inhibition. We expressed chimeric constructs with subunit dimers, to control the number and position of the incorporated chimeric subunits. Surprisingly, incorporation of a subunit with an altered E loop had similar effects whether it contributed either to an intersubunit interface containing a canonical ACh-binding site or to an alternative interface. The observation that the α4 E loop is involved suggests that physostigmine interacts with regions of subunits that contribute to the ACh-binding site, while the lack of interface specificity indicates that interaction with a particular ACh-binding site is not the critical factor.
- Synthetic analogs of stryphnusin isolated from the marine sponge Stryphnus fortis inhibit acetylcholinesterase with no effect on muscle function or neuromuscular transmission. [Journal Article]
- OBOrg Biomol Chem 2016 Nov 29; 14(47):11220-11229
- The marine secondary metabolite stryphnusin (1) was isolated from the boreal sponge Stryphnus fortis, collected off the Norwegian coast. Given its resemblance to other natural acetylcholinesterase an...
The marine secondary metabolite stryphnusin (1) was isolated from the boreal sponge Stryphnus fortis, collected off the Norwegian coast. Given its resemblance to other natural acetylcholinesterase antagonists, it was evaluated against electric eel acetylcholinesterase and displayed inhibitory activity. A library of twelve synthetic phenethylamine analogs, 2a-7a and 2b-7b, containing tertiary and quaternary amines respectively were synthesized to investigate the individual structural contributions to the activity. Compound 7b was the strongest competitive inhibitor of both acetylcholinesterase and butyrylcholinesterase with IC50 values of 57 and 20 μM, respectively. This inhibitory activity is one order of magnitude higher than the positive control physostigmine, and is comparable with several other marine acetylcholinesterase inhibitors. The physiological effect of compound 7b on muscle function and neuromuscular transmission was studied and revealed a selective mode of action at the investigated concentration. This data is of importance as the interference of therapeutic acetylcholinesterase inhibitors with neuromuscular transmission can be problematic and lead to unwanted side effects. The current findings also provide additional insights into the structure-activity relationship of both natural and synthetic acetylcholinesterase inhibitors.
- Reversal of cardiac vagal effects of physostigmine by adjunctive muscarinic blockade. [Journal Article]
- NNeurotoxicology 2016; 57:174-182
- Pre-treatment with reversible acetylcholinesterase (AChE) inhibitors is an effective strategy for reducing lethality following organophosphate nerve agent exposure. AChE inhibition may have unwanted ...
Pre-treatment with reversible acetylcholinesterase (AChE) inhibitors is an effective strategy for reducing lethality following organophosphate nerve agent exposure. AChE inhibition may have unwanted cardiac side effects, which could be negated by adjunctive anti-cholinergic therapy. The aims of the present study were to examine the concentration-dependent effects of physostigmine on cardiac responses to vagus nerve stimulation (VNS), to test whether adjunctive treatment with hyoscine can reverse these effects and to assess the functional interaction and electrophysiological consequences of a combined pre-treatment. Studies were performed in an isolated innervated rabbit heart preparation. The reduction in heart rate with VNS was augmented by physostigmine (1-1000nmol/L), in a concentration-dependent manner - with an EC50 of 19nmol/L. Hyoscine was shown to be effective at blocking the cardiac responses to VNS with an IC50 of 11nmol/L. With concomitant perfusion of physostigmine, the concentration-response curve for hyoscine was shifted downward and to the right, increasing the concentration of hyoscine required to normalise (to control values) the effects of physostigmine on heart rate. At the lowest concentration of hyoscine examined (1nmol/L) a modest potentiation of heart rate response to VNS (+15±3%) was observed. We found no evidence of cardiac dysfunction or severe electrophysiological abnormalities with either physostigmine or hyoscine alone, or as a combined drug-therapy. The main finding of this study is that hyoscine, at concentrations greater than 10(-8)M, is effective at reversing the functional effects of physostigmine on the heart. However, low-concentrations of hyoscine may augment cardiac parasympathetic control.
- Cholinergic modulation of the paraFacial respiratory group. [Journal Article]
- JPJ Physiol 2016 Nov 3
- Active inspiration and expiration are opposing respiratory phases generated by two separate oscillators in the brainstem; inspiration driven by a neuronal network located in the preBötzinger Complex ...
Active inspiration and expiration are opposing respiratory phases generated by two separate oscillators in the brainstem; inspiration driven by a neuronal network located in the preBötzinger Complex (preBötC) and expiration driven by a neuronal network located in the paraFacial Respiratory Group (pFRG). While continuous activity of the preBötC is necessary for maintaining ventilation, the pFRG behaves as a conditional expiratory oscillator, being silent in resting conditions and becoming rhythmically active in presence of increased respiratory drive (e.g., hypoxia, hypercapnia, exercise, or through release of inhibition). Recent evidence from our laboratory suggests that expiratory activity in the principal expiratory pump muscles, the abdominals, is modulated in a state-dependent fashion, frequently occurring during periods of REM sleep. We hypothesised that acetylcholine, a neurotransmitter released in wakefulness and REM sleep by mesopontine structures, contributes to the activation of pFRG neurons and thus acts to promote the recruitment of expiratory abdominal muscle activity. We investigated the stimulatory effect of cholinergic neurotransmission on pFRG activity and recruitment of active expiration in vivo under anaesthesia. We demonstrate that local application of the acetylcholinesterase inhibitor physostigmine into the pFRG potentiated expiratory activity. Furthermore, local application of the cholinomimetic carbachol into the pFRG activated late expiratory neurons and induced long lasting rhythmic active expiration. This effect was completely abolished by pre-application of the muscarinic antagonist scopolamine, and more selective M3 antagonists 4DAMP and J104129. We conclude that cholinergic muscarinic transmission contributes to excitation of pFRG neurons and promotes both active recruitment of abdominal muscles and active expiratory flow. This article is protected by copyright. All rights reserved.
- Optimal Pre-treatment for Acute Exposure to the Organophosphate Dicrotophos. [Journal Article]
- CPCurr Pharm Des 2016 Oct 27
- CONCLUSIONS: These data indicate that K-27 can be considered a very efficacious prophylactic agent for organophosphate exposure.
- Anti-acetylcholinesterase activity of essential oils and their major constituents from four Ocimum species. [Journal Article]
- ZNZ Naturforsch C 2016 Nov 1; 71(11-12):393-402
- Ocimum is a genus of considerable importance in traditional medicine worldwide. The goal of this study was to examine the anti-acetylcholinesterase activity of Ocimum essential oils and to correlate ...
Ocimum is a genus of considerable importance in traditional medicine worldwide. The goal of this study was to examine the anti-acetylcholinesterase activity of Ocimum essential oils and to correlate the activity with their chemical profiles using a metabolome based GC-MS approach coupled to chemometrics. Further, molecular docking was adopted to rationalize the activity of some essential oil isolates. Essential oil prepared from the four species O. basilicum, O. africanum, O. americanum, and O. minimum exhibited significant anti-acetylcholinesterase activity with (IC50 0.22, 0.175, 0.57 and 0.152 mg/mL, respectively) comparable to that of physostigmine (IC50 0.27 mg/mL). The phenylpropanoids (i.e. estragole) constituted the most dominant chemical group in O. basilicum (sweet basil) and O. minimum, whereas camphor (a ketone) was the most abundant in O. africanum and O. americanum. Supervised and unsupervised multivariate data analyses clearly separated O. africanum and O. americanum from other accessions, with estragole, camphor and, to less extent, β-linalool contributing to species segregation. Estragole was found the most active AchE inhibitor (IC50 0.337 µM) followed by cineole (IC50 2.27 µM), camphor (IC50 21.43 µM) and eugenol (IC50 40.32 µM). Molecular docking revealed that these compounds bind to key amino acids in the catalytic domain of AchE, similar to standard drugs.
- Pretreatment and prophylaxis against nerve agent poisoning: Are undesirable behavioral side effects unavoidable? [Review]
- NBNeurosci Biobehav Rev 2016 Oct 20; 71:657-670
- The threat of chemical warfare agents like nerve agents requires life saving measures of medical pretreatment combined with treatment after exposure. Pretreatment (pyridostigmine) may cause some side...
The threat of chemical warfare agents like nerve agents requires life saving measures of medical pretreatment combined with treatment after exposure. Pretreatment (pyridostigmine) may cause some side effects in a small number of individuals. A comprehensive research on animals has been performed to clarify effects on behavior. The results from these studies are far from unambiguous, since pyridostigmine may produce adverse effects on behavior in animals in relatively high doses, but not in a consistent way. Other animal studies have examined the potential of drugs like physostigmine, galantamine, benactyzine, trihexyphenidyl, and procyclidine, but they all produce marked behavioral impairment at doses sufficient to contribute to protection against a convulsant dose of soman. Attempts have also been made to develop a combination of drugs capable of assuring full protection (prophylaxis) against nerve agents. However, common to all combinations is that they at anticonvulsant doses cause behavioral deficits. Therefore, the use of limited pretreatment doses may be performed without marked side effects followed by post-exposure therapy with a combination of drugs.
- Physostigmine and Methylphenidate Induce Distinct Arousal States During Isoflurane General Anesthesia in Rats. [Journal Article]
- A&AAnesth Analg 2016; 123(5):1210-1219
- CONCLUSIONS: Unlike methylphenidate, physostigmine does not accelerate time to emergence from isoflurane anesthesia and does not restore righting during continuous isoflurane anesthesia. However, physostigmine consistently decreases BSP during deep isoflurane anesthesia, whereas methylphenidate does not. These findings suggest that activation of cholinergic neurotransmission during isoflurane anesthesia produces arousal states that are distinct from those induced by monoaminergic activation.
- Thiadiazolodiazepine analogues as a new class of neuromuscular blocking agents: Synthesis, biological evaluation and molecular modeling study. [Journal Article]
- EJEur J Med Chem 2016 Sep 30; 126:15-23
- The synthesis, biological evaluation and molecular modeling study of 6,7-dihydro-[1,3,4] thiadiazolo[3,2-a][1,3]diazepine analogues as new class of neuromuscular blocking agents are described. The ne...
The synthesis, biological evaluation and molecular modeling study of 6,7-dihydro-[1,3,4] thiadiazolo[3,2-a][1,3]diazepine analogues as new class of neuromuscular blocking agents are described. The new compounds act via competitive mechanism with ACh which could be reversed by the anticholinesterase - Physostigmine. Compounds GS-53 (30) and AAH1 (33) induced dose-dependent neuromuscular blockade with onset time of 3 and 10 min, ED50 0.15 and 0.36 mmol/kg i.p., respectively, in rats. Compound 30 proved to be as twice as potent as 33 with rapid onset and shorter duration (P < 0.05). Docking profile of 30 and 33 closely resembles HIE-124 (3), in α7β2 nAChR receptor. Molecular modeling analysis indicated that hydrogen bonding to Thr120 and Thr124 beside hydrophobic interactions play effective role incorporating the active ligands to nAChR. The obtained model could be useful for further development of new skeletal muscle relaxants.
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- Composition and cytotoxic and antioxidant activities of the oil of Piper aequale Vahl. [Journal Article]
- LHLipids Health Dis 2016 Oct 7; 15(1):174
- CONCLUSIONS: The higher cell growth inhibition induced by the oil of P. aequale is probably due to its primary terpene compounds, which were previously reported in the proliferation inhibition, in stimulation of apoptosis and induction of cell cycle arrest in malignant cells.