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Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
As in other cases, allosteric drugs may be classified as covalent (see below) or noncovalent. To the latter belong the benzodiazepines, the non-benzodiazepine Z-drugs (zopiclone, zolpidem, etc.) or barbiturate drugs, targeting the ionotropic GABA receptor and acting as positive allosteric modulator molecules that increase the activity of the GABAA receptor protein in the central nervous system (e.g., Henschel et al., 2008). Cinacalcet is a positive G-protein-coupled receptor (GPCR) modulator that enhances Ca2+ activation of calcium-sensing receptor (Brown, 2010) and is employed to treat hyperparathyroidism; the cellular mechanisms for allosteric modulation of calcium-sensing receptors has been discussed by Cavanaugh et al. (2012). Maraviroc is a negative modulator of the GPCR chemokine receptor CCR5 and used for the treatment of HIV-type 1 (Conn et al., 2009, and literature cited therein). Metabotropic glutamate receptors (mGluRs, several different groups) involved in the modulation of synaptic transmission and neuronal excitability are members of the GPCR superfamily; mGluRs are drug targets of positive allosteric modulators for treating neurological and psychiatric disorders (Alzheimer’s, anxiety, schizophrenia, etc.) as reviewed by Niswender and Conn (2010), Wood et al. (2011), or Herman et al. (2012). A recent example are allosteric BCR-ABL tyrosine kinase fusion protein inhibitors in Philadelphia chromosome-positive acute lymphoblastic leukemia, developed to overcome resistance towards drugs like imatinib and others (Hantschel, 2012). For covalent allosteric inhibitors see the next section.
Climate Change Effects on the Physiology and Ecology of Fish
Published in Donat-P. Häder, Kunshan Gao, Aquatic Ecosystems in a Changing Climate, 2018
What is the underlying mechanism linking high CO2 to these diverse responses? Nilsson et al. (2012) found that abnormal olfactory preferences and loss of behavioral lateralization exhibited by two species of larval coral reef fish exposed to high CO2 can be rapidly and effectively reversed by treatment with an antagonist of the GABAA receptor. It suggests that ocean acidification changes the function of the GABAA receptor which affects the neural activity of the larvae. The GABAA receptor is an important inhibitory receptor in the central nervous system. After combining with agonists, the decoupling Cl–, HCO3– channels open and the negative ions internal flow hyperpolarizes the neurons (decreased excitation). However, in the process of fetal brain development or in some epilepsy cases of human, following the change of Cl–, HCO3– concentration gradient between the inside and outside of the membrane, there is an outflow of anions when GABAA receptor channels open. The neurons appear depolarized (increased excitation) (Farrant and Kaila 2007). In acidifying water, the fish will accumulate HCO3– and expel Cl– to avoid the acidic effect (Ishimatsu et al. 2008, Brauner and Baker 2009). The acid-base adjustment of fish will change the anion flow direction after the GABAA receptor is activated. Its function will change from hyperpolarization to depolarization which will reverse the behavior of prey fish when it faces predators. The apparent link between CO2-induced behavioral disturbances and the GABAA receptor has been supported by several other studies, using an array of sensory and behavioral assays as well as different GABAA receptor antagonists and agonists (Chung et al. 2014, Chivers et al. 2014). Examination of acid-base balance disturbances and associated compensatory mechanisms have also been performed at ocean acidification relevant scenarios. Spiny damselfish (Acanthochromis polyacanthus) exposed to 1,900 μatm CO2 for 4 d exhibited significantly increased intracellular and extracellular HCO3– concentrations and elevated brain pH compared to control fish, providing evidence of CO2 compensation. Moreover, high CO2-exposed fish showed significantly olfactory abnormality, supporting a potential link between behavior disruption and CO2 compensation (Heuer et al. 2016).
What do you mean ‘anxiety’? Developing the first anxiety syndrome biomarker
Published in Journal of the Royal Society of New Zealand, 2018
First let us consider a group of drugs that are generally classed by clinicians as ‘anxiolytics’ (i.e. they are used for the treatment of anxiety, as opposed to panic or depression): benzodiazepines; buspirone; and pregabalin. Any one drug in this group may be muscle relaxant, anti-convulsant, headache-inducing, anti-panic, anti-depressant or addictive. But in no case (dark blue arrows) do all three types of anxiolytic produce all these effects; while all are similarly (moderately) effective in treating generalised anxiety disorder (GAD). Importantly, these ‘anxiolytic drugs’ achieve their actions through quite different pharmacological systems: benzodiazepines modulate the GABAA receptor; buspirone modulates the 5HT1A receptor; and pregabalin modulates calcium channels. These pharmacological variations account for the variation in their side-effect profiles; while their common effect on anxiety is the result of a common final action on neural pathways that control anxiety.
Structure–activity relations for antiepileptic drugs through omega polynomials and topological indices
Published in Molecular Physics, 2022
Medha Itagi Huilgol, V. Sriram, Krishnan Balasubramanian
Epilepsy is one of the leading neurological diseases that has affected more than 50 million people worldwide, and it continues to pose significant challenges for drug discovery and administration. Epilepsy is often a chronic neurological disease that is somewhat less understood in terms of the underlying causes and mechanisms. It is characterised by abrupt seizures that are not related either to high fever such as febrile seizures in young children or other explicable seizures caused by substance withdrawal. A number of other types of sudden seizures are classified as epilepsy, and these seizures could vary from several seizure types and epilepsy syndromes such as Lennox-Gastaut syndrome (LGS). Many of these seizures could be life shortening or life threatening. It is undeniable that epilepsy can impact the quality of life without proper therapeutic intervention. Consequently, understanding epilepsy, antiepileptic drug discovery and administration for this neurological disease have been the focus of several studies over the years [1–7]. Therapeutic administration requires understanding the underlying causes and the types of seizures such as focal seizures, generalised seizures (tonic, atonic, myoclonic, clonic, etc.,) and neonatal seizures. Diagnostic tools such as EEG, brain study and high contrast brain MRI are some of the primary tools that facilitate the diagnosis for early therapeutic intervention. Therapeutic intervention of epilepsy often involves the administration of multiple drugs that include a primary first-line agents and adjunctive therapeutic agents. At present, there are a few proposed mechanisms for the drug action for treating epilepsy [1–7]. Some of the antiepileptic drugs (AED) act as GABAA potentiators, that is, drugs that strengthen the nerve impulses pertinent to the gamma aminobutyric acid (GABA)A receptor. It is well known that for mammals GABA is the dominant inhibitory neurotransmitter and its primary receptor is the GABAA receptor, which is characterised by a ligand-gated Cl- that is opened upon GABA release. Hence many AEDs such as valproate, vigabatrin, toprimate, phenobarbitals, and all–zepams, etc., target the GABAA receptors. The other prominent mechanism of AED action is through blocking of Na+ or Ca2+ channels. Finally, the glutamate (the other amino acid involved in neurotransmitter mediation) inhibitors are yet another group of AEDs, for example, valproate, toprimate, parempanel, etc. Typically, AEDs contain suitable electronic features or functional groups that enact the desired mechanisms for the intended targets which could be GABAA or Na+/Ca2+ channel blockade or Glutamate inhibitors. A common needed feature for almost all AEDs is their propensity to cross the blood–brain–barrier in order for them to reach the target and act as potent neurological drugs. Typically drugs that simultaneously cause multiple actions such as GABAA potentiation, glutamate inhibition, sodium and calcium ion blockades are employed as the primary line of drugs in combination with adjunctive therapeutic AEDs which are more selective in the mechanism of action.