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Targeting the Nervous System
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
Consider the processes taking place in the cholinergic signalling system, as messages are transmitted between neurones or from a neurone to an organ, such as a muscle, across a synapse, using the neurotransmitter acetylcholine. The neurotransmitter is released from the presynaptic neurone during an action potential. The acetylcholine molecules travel across the synaptic cleft and must bind to cholinergic receptors in the membrane of the postsynaptic neurone. This then leads to processes that propagates an action potential in this nerve. The cholinergic receptor therefore presents an attractive target for drugs that can be designed to influence the nervous system.
The patient with acute neurological problems
Published in Peate Ian, Dutton Helen, Acute Nursing Care, 2020
Cholinergic receptors are divided into two subtypes: nicotinic receptors and muscarinic receptors. Most organs are innervated by sympathetic and parasympathetic fibres. The major exception is the vascular system, which is generally under sympathetic control. The systemic effects of the sympathetic and parasympathetic nervous system can be seen in Table 9.1.
Cholinergic Agonists
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Rupali Patil, Aman Upaganlawar
Muscarinic and nicotinic are mainly two subtypes of cholinergic receptors (Fig. 1.2). The effects of parasympathetic nerve discharge are mimicked by the alkaloid muscarine. Parasympathomimetic effects are effects of muscarine at autonomic neuroeffector junctions and are facilitated by mAChRs (Katzung et al., 2009). Autonomic ganglia and skeletal muscle neuromuscular junctions (NMJs) are stimulated by low concentrations of the alkaloid nicotine due to stimulation of nicotinic receptors (nAChRs). But nicotine does not stimulate autonomic effector cells (Katzung et al., 2009).
Acute organophosphate and carbamate pesticide poisonings – a five-year survey from the National Poison Control Center Of Serbia
Published in Drug and Chemical Toxicology, 2023
Žana M. Maksimović, Jasmina Jović-Stošić, Slavica Vučinić, Nataša Perković-Vukčević, Gordana Vuković-Ercegović, Ranko Škrbić, Miloš P. Stojiljković
With energetic supportive measures (securing a breathing line), poison removal and detoxification (gastric lavage until obtaining clear lavage liquid, application of activated charcoal) and symptomatic therapy, specific treatment of OPP poisoning include administration of antidotes (atropine, oximes, diazepam) (Vanova et al.2018, Eddleston 2019, Jokanović et al.2020). Atropine, which has a 100 times stronger affinity for cholinergic receptors than ACh, alleviates the muscarinic effects but has no impact on the nicotinic ones. It is given for as long as there are signs of acute cholinergic crisis, that is until the signs of atropinization occur (Henretig et al.2019). Oximes, AChE reactivators, bind to OPP already bound to AChE, which leads to the reactivation of AChE. The affinity of oximes for different organophosphorus compounds (OPCs) varies significantly. Globally, pralidoxime (PAM-2) is the oxime most frequently used for the treatment of OPP poisoning. Apart from that, in practice, obidoxime (LüH-6) is also used and it is considered the most effective oxime against OPP poisonings (Worek et al.2020, Maksimović et al.2021). Diazepam inhibits the excitability of the neurons in the CNS; by increasing the effect of GABA, it increases cAMP, decreases the level of cGMP, leading to the cessation of convulsions (Lundy and Magor 1978).
Novel Sunifiram-carbamate hybrids as potential dual acetylcholinesterase inhibitor and NMDAR co-agonist: simulation-guided analogue design and pharmacological screening
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Khalid A. Agha, Nader E. Abo-Dya, Abdul Rashid Issahaku, Clement Agoni, Mahmoud E. S. Soliman, Eatedal H. Abdel-Aal, Zakaria K. Abdel-Samii, Tarek S. Ibrahim
Nowadays, growing numbers of people complain of cognition impairment (CI) arises through degenerative brain disease like Alzheimer (AD) and Parkinsonism. Individuals with CI are usually in need for expensive nursing, safekeeping, and institutional care.1 Various neurotransmitters are known by their ability to modulate cognitive function; thus they represent potential targets for enhancing cognition. Among these neurotransmitters, acetylcholine (ACh) is well known for its central role in critical physiological processes, such as attention, learning, memory, stress response, wakefulness, sleep, and sensory information.2,3 Cholinergic deficit is a reliable early marker in Alzheimer’s disease (AD).4 So the activation of cholinergic receptors is an attractive therapeutic option for Alzheimer patients, this can be achieved by inhibiting degradation of ACh using acetylcholinestrase inhibitor (AChEI) like rivastigmine, tacrine, and donepezil, which were approved for treatment of AD (Figure 1).5,6 However, due to reports hepatoxicity associated with tacrine, it is no longer in use.7
Tacrine and its 7-methoxy derivate; time-change concentration in plasma and brain tissue and basic toxicological profile in rats
Published in Drug and Chemical Toxicology, 2021
Jana Zdarova Karasova, Ondrej Soukup, Jan Korabecny, Milos Hroch, Marketa Krejciova, Martina Hrabinova, Jan Misik, Ladislav Novotny, Vendula Hepnarova, Kamil Kuca
The pharmacodynamics effects of these compounds are not based only on inhibitory action. Their pharmacological effect obviously involves several different pathways. Interaction with cholinergic receptors is a substantial part of the mechanism of action (Adem 1992, Soukup et al. 2011). M1 agonist can modify AD pathology at various levels and may bring long-term therapeutics effects in AD treatment (Fisher et al. 2000, Sepsova et al. 2015). However, the real tacrine mechanism of interaction with muscarinic receptors is still unknown. Its action is probably related to unselective muscarinic antagonism or M1 agonism with parallel M2 antagonism. The muscarinic antagonism on M2 muscarinic receptor leads to an increased releasing of acetylcholine in brain tissue (Fisher et al. 2000, Rusted et al. 2000). This kind of muscarinic interaction provides a promising therapeutic potency in AD treatment. Tacrine derivate 7-MEOTA shows higher affinity to muscarinic receptors than tacrine. From this point of view 7-MEOTA may be considered as more promising compound (Sepsova et al. 2015).