Imaging of Beta-Receptors in the Heart
Robert J. Gropler, David K. Glover, Albert J. Sinusas, Heinrich Taegtmeyer in Cardiovascular Molecular Imaging, 2007
Interpretable β-AR imaging requires a radiolabeled tracer that binds rapidly and tightly (slow koff) to the receptor. However, the binding cannot be so tight that the tracer is irreversibly bound to the receptor nor so rapid that it is first-pass extracted and thus is a measure of delivery by blood flow. A radiotracer antagonist with a KD in the nanomolar range usually meets these requirements (16). As mentioned, the radiotracer must be specific for the β-AR and not bind to other receptors or be taken up nonspecifically in the heart. The image of a high specific activity bound radiopharmaceutical may be sufficient to give an indication of the regional distribution of the receptor within the heart but, by itself, does not provide individual values for the receptor density or affinity. The measured product of receptor density and KD is referred to as the binding potential. It is more useful to know the density of receptor concentration because that is the number of available receptors and is a measure of the potential responsiveness of the system. KD may or may not be an important parameter to determine from imaging, depending on whether or not it changes as part of the disease process. For mixed agonist/antagonist ligands, the starting assumption must be that it does change with disease, but there is little information in humans as yet.
Cardiovascular PET-CT
Yi-Hwa Liu, Albert J. Sinusas in Hybrid Imaging in Cardiovascular Medicine, 2017
From the reconstructed tomographic images, the spatial and temporal distributions of the radiotracer in the organ of interest are obtained. With the appropriate corrections, calibration, and knowledge of the specific activity (GBq/mmol) of the administered tracer, the isotope activity or tracer molar concentration per unit of tissue volume (Bq/cc or mmol/L) can be assessed quantitatively. Semiquantitative biodistribution analysis can also be performed, where the activity concentration is normalized by the total amount of activity injected and the subject body weight to determine the standard uptake value in g/cc or g/mL. Additionally, dynamic PET imaging can be used to assess in vivo physiology, biochemistry, or receptor binding of a tracer by quantifying properties such as organ perfusion (mL/min/g), substrate metabolism (mol/min/g), receptor density (pmol/cc), or receptor-ligand binding potential (Bmax/Kd) (Beauregard et al. 2007).
Novel imaging techniques
Harald Breivik, William I Campbell, Michael K Nicholas in Clinical Pain Management, 2008
Early opioid ligand studies showed decreased binding in chronic pain patients that normalized after reduction of their pain symptoms.26 Regional differences in ligand binding within key pain processing brain regions have also been reported in several neuropathic pain studies.27,28 A study of restless legs syndrome found that the opioid-binding potential is negatively correlated with the affective dimension of the McGill Pain Questionnaire.29 A recent study by Maarrawi and colleagues30 demonstrates differential brain opioid receptor availability between patients with central and peripheral neuropathic pain. They found a bilateral binding decrease in both patient groups that could reflect endogenous opioid release secondary to their chronic pain, but they also found a more significant and lateralized decrease specific to the central poststroke pain patients, suggestive of opioid receptor loss or inactivation in receptor-bearing neurons. This binding decrease was more extensive than the brain anatomical lesions and not colocalized to them. These findings have important implications because if central and peripheral forms of neuropathic pain differ in the distribution of opioid system changes, this might account for a differential sensitivity to opiates. For all these studies, causation is an issue. Future studies, in particular longitudinal studies that correlate binding potential with pain intensity, are needed to help elucidate whether decreased receptor availability is caused by increased release of endogenous opioids or decreased receptor density.
Target-based in-silico screening of basil polysaccharides against different epigenetic targets responsible for breast cancer
Published in Journal of Receptors and Signal Transduction, 2022
Nancy Bhura, Pawan Gupta, Jeena Gupta
In silico screening is an integral part of drug discovery. In silico screening comprise ligand-based and structure or target-based methods. The ligand-based approach is used biologically active small molecules for drug design but target structure is not used. However, a target-based approach is used target structure [derived from experimental methods like NMR and X-ray crystallography] for drug design, but biologically active small molecules are not used here. Molecular docking is a target-based approach that is used to evaluate the binding potential of the small molecules against the receptor or target. The two most important aspects of the docking are proper fitting of two structures (protein and ligand) and prediction of binding affinity toward the target. This method is extensively used in drug design and discovery to identify novel small molecules against the biological target [18].
Effect of compromised liver function and acute kidney injury on the pharmacokinetics of thymoquinone in a rat model
Published in Xenobiotica, 2020
Khalid M. Alkharfy, Fahad A. Ali, Mohammad A. Alkharfy, Basit L. Jan, Mohammad Raish, Saeed Alqahtani, Ajaz Ahmad
The current study explored for the first time, according to our best knowledge, the influence of compromised hepatic and renal functions on the pharmacokinetics of TQ employing animal models of liver dysfunction and acute kidney injury. The impaired kidney and hepatic functions in the current study was evident by the significantly higher levels of kidney and hepatic systemic biomarkers (i.e., Scr and ALT). The pharmacokinetic data of the normal control rats showed that TQ is rapidly eliminated from the body. The interesting reflection that was seen in the concentration time profile of the IV dosing was the bi-phasic decay of TQ. The early quick decline denotes a rapid drug distribution phase as a consequent binding to both plasma and tissue proteins. A protein binding potential of drug in blood plasma is a very important factor affecting its free concentration in the distribution of blood and tissue (Talbi et al., 2014). TQ has a high degree of protein binding to rat plasma (over 99%), significantly reducing free exposure to the compound. This conversely was accompanied by a relatively small volume of distribution, which can be explained by the high drug binding of TQ to plasma proteins due to its poor water solubility (log P value = 2.55).
A new mixed-ligand coordination polymer: protective activity on influenza a virus-induced COPD via regulating tlr3 gene expression on alveolar epithelial cells
Published in Drug Development and Industrial Pharmacy, 2021
Youhui Tu, Chao Yang, Xiangwei Zhang
Molecular docking method is a tool to help us reflect how the interaction between ligands and receptor proteins preforms at molecular level. Considering the complicated structure of the compound, we truncated the compound and only reserved the functional side chain. As shown in Figure 7, top 4 binding modes were generated with the lowest binding energy, which describes a outline view of the complex offered via the target protein wrapped in a binding bag. Interestingly, four potential binding modes revealed two possible binding sites. The pose 1 (Figure 7(A)) and pose 2 (Figure 7(B)) exhibited similar binding sites with energy contribution of −7.61 and −7.42 kcal/mol, respectively, indicating large possibility for the ligand to bind. While the pose 3 and pose 4 showed a binding potential in another binding site with energy contribution of −5.17 and −5.02 kcal/mol, respectively. Although different binding pockets were observed, the ligand of all the binding modes showed a similar binding patter: the functional sidechain of the carboxyl formed multiple polar interaction, which contributed most binding energy. Thus, the above evidence demonstrated the ligand could recognize the specific sites on TLR3, showing as a rational recognizing group.
Related Knowledge Centers
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