Enzymes
S.J. Mulé, Henry Brill in Chemical and Biological Aspects of Drug Dependence, 2019
In a recent study in our own laboratory, a series of methyl through dodecyl JV-Alkyl substituted normeperidine congeners were studied as inhibitors of both acetyl and butyrylcholinesterase.12 In this study attempts were also made to correlate the physical-chemical parameters of these compounds such as molecular parachors, hemolytic activity, alkyl chain length, and Rm values with both enzyme inhibition and analgesic potency. Like the benzomorphans, the normeperidine congeners were also found to be mixed inhibitors of acetylcholinesterase. In addition, they produced the same type of inhibition with butyrylcholinesterase when acetylcholine was used as substrate. Simple linear relationships were observed with butyrylcholinesterase when alkyl chain length, Rm values, and molecular parachors were plotted as a function of the logarithm of the enzyme inhibitor dissociation constants. More complex relationships were noted with acetylcholinesterase and these parameters. When analgesia was determined as a function of the alkyl chain substituent on the normeperidine molecule, a biphasic correlation was observed between chain length and ED50. Analgesia increased until a chain length of about six carbons was reached and then decreased. These results suggest that the analgesic receptor possesses a definitive nonpolar geometric area that contributes to the binding of the analgesiophore through Van der Waal’s interactions. Small changes in binding energies were reflected as significant increases in analgesic potency.
Multi-Functional Monoamine Oxidase and Cholinesterase Inhibitors for the Treatment of Alzheimer’s Disease
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
Cholinesterases are widespread enzymes found in both cholinergic and non-cholinergic tissues as well as in plasma and other bodily fluids (Massoulié et al., 1993). They are classified into two forms according to their substrate specificity, behaviour in excess substrate and susceptibility to inhibitors (Tarihi et al., 2003). Acetylcholinesterase (AChE) also referred to as ‘true cholinesterase’ is encoded by a gene on chromosome 7 (Aldridge, 1953). It is the more prominent of the cholinesterases and the only one consistently associated with cholinergic pathways. It was found that cholinergic neurons display high AChE enzyme activity in the perikaryon, proximal dendrite and axon (Mesulam and Geula, 1991). AChE is known to be abundantly available in the brain, muscle and erythrocyte membrane (Dave et al., 2000). The second cholinesterase, found mainly in the liver, heart and lungs is called butyrylcholinesterase (BuChE). It is also known as pseudocholinesterase or non-specific cholinesterase and is present in much lower concentrations than AChE with limited distribution in the central nervous system (Dave et al., 2000; Mesulam, 2000). The two cholinesterases present similar soluble molecular forms in tissues and body fluids with differing tissue distribution.
Drugs Affecting Autonomic Ganglia (Including the Adrenal Medulla)
Kenneth J. Broadley in Autonomic Pharmacology, 2017
The elements of Ach synthesis, storage and release, already discussed in Chapter 7, are found at the preganglionic nerve terminals (Figure 7.1). Choline is taken up into the nerve terminal by an active uptake process and synthesis to Ach by the action of choline acetyltransferase (ChAT) occurs in the neuronal cytoplasm. The Ach is then taken up by the storage vesicles which are concentrated at the synaptic varicosities that make contact with the dendrites of the postganglionic nerve cell body. The release of Ach is induced by depolarization of the preganglionic nerve either by a nerve action potential or by high concentrations of K+. The release is exocytotic. Acetylcholinesterases of both the globular (G4) and asymmetric collagentailed form (A12) are found in ganglia and are located both pre- and postjunctionally. Butyrylcholinesterase is found postsynaptically (Buckley & Caulfield 1992). High concentrations of nicotinic Ach receptors are located at the synapse, their aggregation being directed by a protein, agrin. This is present in the cell body and undergoes orthograde transport along the axon to the nerve terminal (Fallon 1991).
Isothiocyanates: cholinesterase inhibiting, antioxidant, and anti-inflammatory activity
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Franko Burčul, Ivana Generalić Mekinić, Mila Radan, Patrick Rollin, Ivica Blažević
Alzheimer’s disease is the most common neurodegenerative disorder in western societies, mostly affecting elderly population. The most prominent symptom includes decrease in cognitive function, which in turn leads to changes in the behavioural patterns of an individual. Both acetylcholinesterase and butyrylcholinesterase still represent the only pharmacotherapy able to affect the increase of the acetylcholine neurotransmitter in the brain1–3. Essential oils, containing small lipophilic molecules, such as terpenes, terpenoids, phenylpropanoids, and others, were increasingly studied lately since they can readily cross the blood-brain barrier4. Interestingly, there are no reports whatsoever on the so called “mustard oils”, the major constituents of which are isothiocyanates (ITCs), known for their diversified and generally marked bioactivity5. Mustard oils stand as bio-markers of Brassica vegetables which encompass many species used in daily diets (cabbage, horseradish, cauliflower, turnip, radish, cress, etc.).
Solanaceae glycoalkaloids: α-solanine and α-chaconine modify the cardioinhibitory activity of verapamil
Published in Pharmaceutical Biology, 2022
Szymon Chowański, Magdalena Winkiel, Monika Szymczak-Cendlak, Paweł Marciniak, Dominika Mańczak, Karolina Walkowiak-Nowicka, Marta Spochacz, Sabino A. Bufo, Laura Scrano, Zbigniew Adamski
In addition, SGAs are potent inhibitors of enzymes involved in the breakdown of the neurotransmitter acetylcholine. Blocking acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) causes the accumulation of acetylcholine in the central nervous system. This could result, e.g., in impaired balance and motor coordination, shortness of breath and increased heart rate (Friedman 2006). SGAs also show high activity in insects. For example, they have substantial effects on the activity of the insect myocardium, affecting not only the frequency and force of insect heart contraction but also the duration of circadian phases of heart activity (Ventrella et al. 2015; Marciniak et al. 2019). Furthermore, SGAs affect the structure of fat body cells and the midgut and change the carbohydrate profile of insect haemolymph (Spochacz et al. 2018, 2020, 2021). Therefore, due to similar effects observed in insects and mammals, insects can serve as good models for testing the effects of these substances on mammals, including humans.
Tucumã (Astrocaryum aculeatum) extract: phytochemical characterization, acute and subacute oral toxicity studies in Wistar rats
Published in Drug and Chemical Toxicology, 2022
Camille Gaube Guex, Gabriela Buzatti Cassanego, Rafaela Castro Dornelles, Rosana Casoti, Ana Martiele Engelmann, Sabrina Somacal, Roberto Marinho Maciel, Thiago Duarte, Warley de Souza Borges, Cínthia Melazzo de Andrade, Tatiana Emanuelli, Cristiane Cademartori Danesi, Euler Esteves Ribeiro, Liliane de Freitas Bauermann
Serum cholinesterase or butyrylcholinesterase can be found in the central and peripheral nervous system and in the liver. Decreased enzyme activity is observed when hepatocellular impairment occurs, since it is synthesized in the liver, which makes it an important biochemical marker of organ damage (Santarpia et al. 2013). Our experiment showed no significant differences between groups, indicating no organ damage. The liver plays an essential role in lipid metabolism, stages of lipid synthesis and transportation, therefore, an abnormal lipid profile may be an indication of severe liver dysfunction (Ghadir et al. 2010). Ferreira et al. (2008) showed that another species of tucumã (A. vulgare) is composed of fatty acids, which may be involved in a reduction of plasma cholesterol, triglycerides, and LDL, as well as an increase of HDL concentration. In our study, treatment with CETP increased HDL levels of males and females and decreased LDL levels of males. Stearic acids are known to act moderately on reducing LDL levels and increasing HDL (Silva et al. 2018). Thus, the results found in this study may be important for future investigations on the use of tucumã extract to treat dyslipidemias, since stearic acid was shown to be present.
Related Knowledge Centers
- Acetylcholinesterase
- Butyrylcholine
- Choline
- Cholinesterase
- Ester
- Blood Plasma
- Gene
- Liver Function Tests
- Pseudocholinesterase Deficiency
- Suxamethonium Chloride