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Finding a Target
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
There are also alternative ways that antagonists can be designed, without complementary binding to the receptor site. In an analogous method to non-competitive enzyme inhibition, allosteric antagonists may bind to a completely different part of the receptor protein, resulting in distortion of the receptor site, which is therefore unable to accommodate the natural substrate. Alternatively, binding can take place with amino acid residues outside of the receptor site and the steric bulk of the drug molecule may block entry to the receptor binding site and prevent access of the natural substrate. This is referred to as the “umbrella effect”. It is a useful strategy because it may be difficult to develop a drug to target the receptor binding site if molecular modelling of this region is unclear.
Antiepileptic Drug Interactions: An Overview
Published in Carl L. Faingold, Gerhard H. Fromm, Drugs for Control of Epilepsy:, 2019
To validate the presence of a pharmacodynamic interaction, it must be established that the concentration of the drug under study is not altered at the receptor site by the comedication. To demonstrate this in humans is exceedingly difficult; most of the evidence for receptor site interactions has come from in vitro binding studies involving preparations of purified receptors. The presence of a binding interaction in these in vitro preparations, however, may not necessarily translate into a clinically meaningful interaction in a complex neuronal network where excitatory enhancement at one type of receptor may be offset by an inhibitory response elsewhere.
Interaction of Drugs of Dependence With Receptors
Published in S.J. Mulé, Henry Brill, Chemical and Biological Aspects of Drug Dependence, 2019
The guinea pig ileum possesses a multiplicity of potential receptor sites for morphine; combination with any one of these would result in blockade of the cholinergic pathway. These include the preganglionic nerve axon, its terminals, postganglionic receptors, postganglionic neuron or axon, its nerve terminal, postsynaptic ACh receptors, the transport mechanism for choline, and cholinesterase (ChE). All but one may be ruled out as a possible receptor site. The entire pathway from preganglionic fibers to ganglion may be blocked by either hexamethonium, chlori-sondamine, or nicotine without changing the action of morphine in any way. AChE affinity for morphine is too weak to account for its effect on transmission; indeed, ChE inhibitors would potentiate rather than inhibit transmission. Addition of choline does not influence inhibition by morphine.29 Finally, at a time when transmission is completely blocked, response of the tissue to ACh is totally unaltered.6,23 Therefore, the effect of morphine is relegated to the postganglionic neuron. In view of the weak local anesthetic activity of morphine, it is anticipated that at the concentrations used to block contractions, the drug would have little, if any, effect on conduction in postganglionic elements. The evidence strongly suggests that the site of morphine action is in the nerve terminal. At this site morphine inhibits the release of ACh either at rest or upon electrical stimulation.23,26
Carcinogenic risk assessment, health endpoint and source identification of heavy metals in Mahshahr, Iran
Published in Toxin Reviews, 2023
Farzaneh Nikfar, Sima Sabzalipour, Ali Gholami, Ahad Nazarpour
Principal component analysis of the main components is an effective method to determine the roles of humans on spatial scales (Keshavarzi et al.2019). PCA has been used extensively in receptor modeling to classify the main potential source categories influencing a provided receptor site. In general, a high correlation coefficient between Zn and Cd indicates pollution emissions associated with imperfect combustion of hydrocarbon fuels, Steel factory, petroleum, human activities and incineration (Pongpiachan and Iijima 2016). In this study, Cu, Zn, Pb, Cd, Cr, Ni, As, and V were used in the analysis of the main components to investigate the differences and precision origins. The loading values of heavy metals indicated a relationship between metals and their components, so that loading values were equal to Pb < Zn < Cd < Cu < As < Ni < V <Cr for the first component, equal to Ni < Cr < As < Zn < Cu < Pb < V <Cd for the second component, and equal to V < Pb < Zn < Ni < Cd < As < Pb < Cr for the third component. These arrangements were particularly important, and they were reflected in the degree of influence and control of each component in each element. The analysis results of the main components of the studied heavy elements showed that the first component with the highest loading value played a crucial role in determining the source of pollution in the studied region.
Antibiotic uptake through porins located in the outer membrane of Gram-negative bacteria
Published in Expert Opinion on Drug Delivery, 2021
Antibiotic activity requires sufficient high concentrations at the target site which depends crucially on the permeability of the outer cell wall. Cell wall permeability is not a simple set of parameter but rather a dynamic result of numerous origins. Permeability change during the cell cycle but may also vary from bacteria to bacteria within the same cell culture. Slight genetic variation and responses to environmental condition (media, temperature, pH etc) may rapidly lead to an advantage in growth and amplification. To achieve comparable values, one needs a careful analysis of the condition of the measurement. The biological or pharmacological relevant overall parameter is the accumulation of a critical concentration at the receptor site. As this critical threshold varies in time and on site of infection the goal should be to maximize the effective uptake for a broad set of condition. Complex data analysis (machine learning) may help but depend in one way on the right set of information on the rate-limiting steps [82]. Note, here in this review we focus our opinion mainly on physico-chemical aspects.
Modulation of xenobiotic metabolizing enzyme activities in rat liver by co-administration of morin, endosulfan, and 7,12-dimethylbenz[a]anthracene
Published in Drug and Chemical Toxicology, 2020
Canan Sapmaz, Tulin Firat, Aysel Kukner, Azra Bozcaarmutlu
The highest EROD activity was obtained when all three chemicals were administered together (Figure 1). Elevated EROD activities in this group indicate that morin, endosulfan, and DMBA stimulated CYP1A1 synthesis in rat liver. The stimulatory effects of these chemicals were also observed when given alone. We expected to see an additive effect in the combinations of these chemicals. However, EROD activities measured in the rats exposed to the triple administration of these compounds were less than the additive effect. CYP1A induction is under the control of aryl hydrocarbon receptor (Chatuphonprasert et al. 2010). Molecules may compete with each other to bind the same receptor site, and the presence of the other molecules may prevent interaction of another with the aryl hydrocarbon receptor. The CYP3A-associated erythromycin N-demethylase activity increased in the triple administration group with respect to DMBA + endosulfan. High GST activity was obtained in the triple administration group of morin, endosulfan, and DMBA relative to DMBA + endosulfan. The protective effect of morin was also observed in the results of histopathological studies. Endosulfan and DMBA stimulated inflammation in the liver tissues, and morin reduced their effects.