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Radiolabeled Enzyme Inhibitors
Published in William C. Eckelman, Lelio G. Colombetti, Receptor-Binding Radiotracers, 2019
No evidence for the in vivo sequestration of any of these compounds in the adrenal cortex could be found in the literature. Thus the most promising inhibitors were radiolabeled by incorporating tritium in their aromatic rings by acid catalyzed exchange methods or by l25I labeling.16 The tissue distributions of the radiolabeled enzyme inhibitors were determined in dogs at various time intervals. Table 4 summarizes the concentrations of radioactivity obtained in five major tissues, including the adrenal cortex, with six radiolabeled inhibitors. Figure 5 shows the respective chemical structures of the 3H- or 125I-labeled inhibitors that were evaluated in the study. Of the tritiated inhibitors evaluated, 3H-SKF-12185 and 3H-metyrapone showed adrenal cortex-to-liver concentration ratios ranging from only 4 to 8, suggesting competitive binding to hepatic P-450. The possible stereospecificity of in vivo adrenocortical P-450 binding was probed by evaluation of the distribution of the 125I-labeled enantiomers of SKF-12185. As revealed in Table 5, the I-isomer showed twice the adrenocortical affinity of the d-isomer and nearly a threefold increase in the adrenal cortex-to-liver concentration ratio. This result could also be explained by a higher metabolic rate for the d-isomer. However similar results have been obtained at shorter time intervals when metabolic rate differences between the two enantiomers should be minimal.
Hallucinogens, CNS Stimulants, And Cannabis
Published in S.J. Mulé, Henry Brill, Chemical and Biological Aspects of Drug Dependence, 2019
The most widely known drug of this entire group is the semisynthetic compound, lysergic acid diethylamide, LSD-25. The stereochemical structure of the active (d-) isomer is shown in Figure 1. Although the chemical was first synthesized in 1937, its extraordinary activity was not recognized until 1943,1 and not reported until 1947.2,3 Within a few years, it had been introduced and received broad experimental evaluation within both medical and experimental social circles of the U. S.
Aspartic Acid Racemization and Aging in Cartilaginous Tissue
Published in Sara C. Zapico, Mechanisms Linking Aging, Diseases and Biological Age Estimation, 2017
Sarit Sara Sivan, Alice Maroudas, Ellen Wachtel
where CAsp is the molar concentration of Asp in the protein and D/(D+L) and L/(D+L) represent the fractions of the D- and L-isomers, respectively. Assuming that the content of the D-isomer is so small that D/(D+L) ≈ (D/L) and L/(D+L) ≈ 1, which is usually the case in vivo, Equation (1) can be rewritten as:
Comparison of the Bone Regenerative Capacity of Three-Dimensional Uncalcined and Unsintered Hydroxyapatite/Poly-d /l -Lactide and Beta-Tricalcium Phosphate Used as Bone Graft Substitutes
Published in Journal of Investigative Surgery, 2021
Yunpeng Bai, Jingjing Sha, Takahiro Kanno, Kenichi Miyamoto, Katsumi Hideshima, Yumi Matsuzaki
The composite 3D-HA/PDLLA is polymerized from u-HA, the two stereoisomers of polylactic acid (PLA), high-molecular-weight bioresorbable polymer poly-d-lactic acid (PDLA), and PLLA [13]. The properties of the resulting polymer depend on the dextrorotatory (D) and levorotatory (L) configurations [14]. The l-isomer is characterized by higher crystallinity and less rapid resorption, whereas the d-isomer is characterized by more rapid resorption and a less crystalline structure [15]. Hence, PDLLA combines the advantages of PDLA and PLLA, which is why these composites exhibit sufficient plasticity to modify various scaffold shapes and prevent their rapid destruction following implantation [16]. Based on our previous research, 3D-HA/PDLLA performs well in vitro; showing an excellent capability to promote preosteoblast MC3T3-E1 cell proliferation and differentiation [17]. After cell culture for 48 h, the Alamar Blue reduction rate increased over four times from time zero. During the follow-up period, the genes Runt-related transcription factor 2 (Runx2) and Osterix (Sp7) were upregulated dramatically in 3D-HA/PDLLA compared with dense-HA/PDLLA, which contains a homogeneous mixture of HA/PDLLA but lacks internal pores. However, the in vivo study showed identical bone reformation in 3D-HA/PDLLA and beta-tricalcium phosphate (β-TCP). Furthermore, the expression of bone transcriptional factors such as Runx2 and osteocalcin (OCN) in the 3D-HA/PDLLA and β-TCP groups was not compared in our previous study [17].
Pharmacokinetics and pharmacodynamics of dextromethorphan: clinical and forensic aspects
Published in Drug Metabolism Reviews, 2020
Ana Rita Silva, Ricardo Jorge Dinis-Oliveira
DXM (3-methoxy-N-methylmorphinan; Figure 1) is the dextrorotatory [d- or (–)] enantiomer of levomethorphan [l- or (+)], which is the methyl ether of DXO (3-hydroxy-N-methylmorphinan) and levorphanol, respectively (Sromek et al. 2014). Although former levorotatory compounds are both opioid analgesics, only levorphanol was clinically developed (Gudin et al. 2016; Le Rouzic et al. 2019). Moreover, levorphanol is the levorotatory isomer of racemic 3-hydroxy-N-methylmorphinan (Dromoran®) and named as Levo-Dromoran®. DXM is named according to IUPAC rules as (+)-3-methoxy-17-methyl-9α,13α,14α-morphinan. It is also the d-isomer of methorphan (racemic mixture), but unlike the l-isomer, it does not have opioid activity. Methorphan presents as two isomeric forms, each with differing pharmacology and effects with respect to its two enantiomers. The DXM is used as an antitussive drug in cough medicines (and in high doses, it is a dissociative hallucinogen), whereas the levorotatory enantiomer levomethorphan, a prodrug of levorphanol, is a strong opioid analgesic that is listed as a schedule II drug in the USA (Wong and Sunshine 1996; Bortolotti et al. 2013; Gudin et al. 2016). Levorphanol binding affinity for the mu (MOR; µ) opioid receptor, 0.42 nM, is greater than the affinity of morphine, 1.24 nM and also presents longer t1/2 (Bortolotti et al. 2013). As DXM is approved for use in OTC drugs, accurate control of enantiomeric purity is essential to assure that commercial DXM preparations do not contain the l-enantiomer.
The apelin/APJ system as a therapeutic target in metabolic diseases
Published in Expert Opinion on Therapeutic Targets, 2019
Isabelle Castan-Laurell, Bernard Masri, Philippe Valet
The weak stability of apelin fragments, consistent with transient effects of apelin forms observed in vivo, has promoted the development of metabolically stable apelin analogs through different approaches. These modifications consist of amino acid replacement by its D-isomer or an unnatural amino acid [96–99], acetylation of the N-terminus [23,97], amidation of the C-terminus in association with peptide palmitoylation [23] or not [24], polyethylene glycosylation [54,100], addition of a fluorocarbon chain [97] or palmitic acid [101] to the N-terminus but also cyclization [95,102,103]. These compounds and others have been described in more details in a recent review [104]. Those different modifications considerably increased the half-life of the peptides from several minutes to more than 24 h. Stabilized apelin analogs resulted in longer and better activity in vivo as observed for diuretic, cardiovascular effects and blood glucose lowering when compared to native apelin fragments [23,54,97,98]. Concerning long-term analogs effects on energy metabolism, four weeks treatment in obese/insulin-resistant mice with recombinant protein by fusing IgG Fc fragment to apelin-13 [105] or with acylated apelin-13 analogs [106] resulted in improvement of glucose tolerance and decreased hepatic steatosis for the first compound and a better lipid profile and insulin sensitivity for the second, in line with results obtained during long-term apelin treatment [42,48].