Finding a Target
Nathan Keighley in Miraculous Medicines and the Chemistry of Drug Design, 2020
Drugs that target enzymes are designed to inhibit their normal operation. This can be achieved in different ways. Competitive inhibitors mimic the molecular structure of normal substrate so that the drug can bind with a complimentary fit to the active site of the enzyme. This has the effect of blocking the active site, preventing entry of the normal substrate. The necessary reaction with the normal substrate cannot proceed, hence the biological process is subdued. The extent of this effect depends on the concentration of the drug, which in turn determines how many active sites are inhibited out of the plethora of catalytically available enzymes. Also important is the strength of binding of the drug to the active site, which effects the length of time that the drug remains in the active site; impacting the probability of normal biological catalysis happening. The nature of non-covalent interactions; being changeably broken and re-formed results in inhibition occurring dynamically. The weaker the intermolecular forces between the drug and the active site, the greater the proportion of unencumbered enzymes at any one time and the biological process will be inhibited to a lesser extent. The drug must be designed to optimise non-covalent interactions in order to be effective. Alternatively, the drug molecule could perhaps be designed to undergo reaction once in the active site to form a covalent bond to an amino acid residue. This is an irreversible form of inhibition and renders that enzyme molecule redundant.
Neurons
Nassir H. Sabah in Neuromuscular Fundamentals, 2020
Moreover, it is generally true that both LVA and HVA Ca2+ channels are found in the dendrites, soma, and initial segments of neurons, their relative distribution between these regions depending on the type of neuron. Being slower to activate than the Na+ transient current, the Ca2+ currents make little contribution to the rising phase of the AP but become significant during the falling phase. Depending on the channels involved, Ca2+ entry can directly contribute to depolarization, as expected for an inward cationic current, but can also have an opposite effect by activating large-conductance K+ channels. Ca2+ currents at the axon initial segment affect excitability and the generation of bursts of spikes, as well as the speed of repolarization, and hence the width of the generated AP. An interesting aspect of LVA Ca2+ channels is that they are normally inactivated at resting voltage levels. They are deinactivated by hyperpolarization and activated by a subsequent depolarization. As a result of this activation, Ca2+ enter through these channels and further amplify the depolarization. The inhibition–excitation sequence in neurons thus plays an important role under these conditions.
Sympathetic Neurotransmission
Kenneth J. Broadley in Autonomic Pharmacology, 2017
More recently, competitive reversible and short-acting MAO inhibitors have been developed. The effect of these is readily reversed by any procedure that reduces inhibitor concentration. Furthermore, the duration of action will be controlled by its rate of removal by metabolism and elimination because no covalent bond formation is involved. Substrate and inhibitor binding to the enzyme is mutually exclusive and high concentrations of substrate will displace a competitive inhibitor from the enzyme. Examples include brofaromine (CGP 11305A), moclobemide, cimoxatone and toloxatone, which are selective for MAO-A. Ro 19–6327 is a highly potent and reversible selective MAO-B inhibitor (Figure 2.15) (Kyburz 1990).
New drugs under investigation for the treatment of alopecias
Published in Expert Opinion on Investigational Drugs, 2019
Jorge Ocampo-Garza, Jacob Griggs, Antonella Tosti
Apremilast is an oral, small molecule inhibitor of phosphodiesterase 4 (PDE4). Inhibition of PDE4 results in a higher levels of cyclic adenosine monophosphate (cAMP), which reduces the production of many pro-inflammatory mediators [9]. Apremilast is FDA approved for the treatment of psoriasis and psoriatic arthritis, and is currently being tested for AD [42]. In a humanized mouse model of alopecia areata containing human scalp skin, apremilast caused a preservation of hair follicles and downregulation of inflammatory markers [43]. Liu et al. [44] reported a series of nine patients with AA and alopecia universalis treated with apremilast; none of the patients experienced hair growth over a 3- to 6-month treatment. However, Magdaleno-Tapial et al. [42] reported a case of a woman with AA which showed significant scalp hair growth after 15 weeks of treatment with apremilast. A randomized, placebo-controlled, single center pilot study of the safety and efficacy of apremilast in patients with moderate to severe AA is currently in progress (NCT02684123).
Comparison of Intentional Inhibition and Reactive Inhibition in Adolescents and Adults: An ERP Study
Published in Developmental Neuropsychology, 2020
Yue Shen, Hui Zhao, Jiayin Zhu, Yi He, Xue Zhang, Songhan Liu, Jinghan Chen
It is necessary to confirm whether intentional inhibition and reactive inhibition have different neuropsychological processes. These two kinds of inhibition have distinct experimental forms. Previous researches have shown that, reactive inhibition has been commonly associated with increased activity in the fronto-basal ganglia network including the dorsal prefrontal cortex (dPFC), the inferior frontal gyrus (IFG, mostly in the right hemisphere), the pre-supplementary motor area (preSMA) and the basal ganglia (most prominently the dorsal striatum and the sub-thalamic nucleus (Aron, 2011; Bari & Robbins, 2013). Although the activity related to intentional inhibition largely overlaps with the networks characterizing reactive inhibition (Schel, Ridderinkhof, & Crone, 2014), increased activity within the dorsal part of the fronto-median cortex (dFMC) has also been reported, a region that is not involved in reactive inhibition (Brass & Haggard, 2007; Kühn, Haggard, & Brass, 2009; Lynn, Muhle-Karbe, & Brass, 2014; Schel et al., 2014). However, others found that dFMC activation was only observed in reactive inhibition (Lynn, Demanet, Krebs, Van Dessel, & Brass, 2016; Severens, Simone Kühn, Hartsuiker, & Brass, 2012). dFMC’s role and its underlying functions are currently disputed by scholars.
A comprehensive review on tyrosinase inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Samaneh Zolghadri, Asieh Bahrami, Mahmud Tareq Hassan Khan, J. Munoz-Munoz, F. Garcia-Molina, F. Garcia-Canovas, Ali Akbar Saboury
The chemical structure of the different substrates is diverse, but the process always requires a step of oxidation/reduction: o-diphenols102,104, ascorbic acid103, aminophenols and o-diamines105, hydroxyhydroquinone109, tetrahydrobiopterines110, tetrahydrofolic acid111 and NADH112.Generally, the mode of inhibition by “true inhibitors” is one of these four types: competitive, uncompetitive, mixed type (competitive/uncompetitive), and noncompetitive. A competitive inhibitor can bind to a free enzyme and prevents substrate binding to the enzyme active site. Regarding the property that tyrosinase is a metalloenzyme, copper chelators such as many aromatic acids, phenolic and poly-phenolic compounds, a few non-aromatic compounds, can inhibit tyrosinase competitively by mimicking the substrate of tyrosinase52,60. Recently, it was found that d-tyrosine negatively regulates melanin synthesis by inhibiting tyrosinase activity, competitively113. In addition, l-tyrosine has been shown as an inhibitor114.
Related Knowledge Centers
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