China
Africa
Explore chapters and articles related to this topic
Disposition and Metabolism of Drugs of Dependence
Published in S.J. Mulé, Henry Brill, Chemical and Biological Aspects of Drug Dependence, 2019
Approximately 4% of methadone is excreted free in urine and 5% in feces of man given 20 mg orally and in the rat.264 Biliary excretion is an important route for the elimination of methadone and its metabolites.264N-demethylation is an important metabolic pathway for methadone in vitro107 and in vivo.265 Evidence has also been produced for the formation of primary and secondary amine metabolites266 and for N-methylation to a quaternary ammonium compound in vitro to the extent of 15% by guinea pig liver slices.267N-demethylation of methadone to a secondary amine which spontaneously rearranged to form 1,5-dimethyl-3,3-diphenyl-2-ethylidene pyrrolidine (A) as a major metabolite in man has been reported.268 This metabolite was found particularly in bile. Lung tissue localized methadone to the greatest extent. Approximately 60% of the dose in man could be accounted for as methadone and pyrrolidine metabolite. Chromatographic evidence for three other unidentified metabolites has also been obtained.269 Evidence for further metabolism of the above pyrrolidine metabolite to 2-ethyl-5-methyl-3,3’-diphenyl-l-pyrroline (B) has recently been produced.270 These two metabolites have been isolated, characterized and synthesized and found to be pharmacologically inactive.270 In vitro conversion of methadone to its N-oxide has been shown to occur on incubation of methadone with 10,000 × g microsomal supernatant of male guinea pig liver homogenates.271
Synthetic Cathinones and Related Fatalities in the United Kingdom
Published in Ornella Corazza, Andres Roman-Urrestarazu, Handbook of Novel Psychoactive Substances, 2018
John M. Corkery, Christine Goodair, Hugh Claridge
Cathinones are typically categorized based on their pharmacological action or properties or in comparison to ‘traditional’ stimulant drugs. Some classifications consider their effects in relation to different substrates or non-substrate transporter inhibitors (Simmler et al., 2013). Others draw comparisons with ecstasy/MDMA, amphetamine/ methylamphetamine, and cocaine (Concheiro, Anizan, Ellefsen, & Huestis, 2013) or combinations, such as MDMA/cocaine, together with chemical structure categories (Valente, Guedes de Pinho, de Lourdes Bastos, Carvalho, & Carvalho, 2014; Concheiro et al., 2013; Assi, Gulyamova, Kneller, & Osselton, 2017). Some classifications regard pyrrolidines as a separate category.
Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Selective estrogen receptor modulators (SERMs) are structurally different compounds that interact with intracellular estrogen receptors in target organs as estrogen agonists and antagonists. The molecular basis of SERM activity involves binding of the ligand SERM to the estrogen receptor, causing conformational changes that facilitate interactions with coactivator or corepressor proteins and later initiate or suppress transcription of target genes (Shelly et al. 2008). SERMs currently approved for use in patients include tamoxifen, raloxifene, and toremifene. Tamoxifen, a triphenylethyleneamine derivative, is one of the most widely used SERMs for the treatment of postmenopausal, hormone-sensitive, estrogen receptor–positive breast cancer (Jordan 2007; Jordan and O’Malley 2007). Tamoxifen is first approved in 1977 by the US FDA for the treatment of meta-static breast cancer and in ensuing years for adjuvant treatment of breast cancer. Other triphenylethylene SERMs, analogs of tamoxifen, have been studied for breast cancer prevention and treatment, including droloxifene (3-hydroxytamoxifen) (Buzdar et al. 2002; Roos et al. 1983; Ruenitz et al. 1982), idoxifene (pyrrolidino-4-iodotamoxifen) (Arpino et al. 2003; Chander et al. 1991; Coombes et al. 1995; Johnston et al. 2004), and ospemifene (Komi et al. 2005).
Novel benzothiazole derivatives as multitargeted-directed ligands for the treatment of Alzheimer’s disease
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Donia E. Hafez, Mariam Dubiel, Gabriella La Spada, Marco Catto, David Reiner-Link, Yu-Ting Syu, Mohammad Abdel-Halim, Tsong-Long Hwang, Holger Stark, Ashraf H. Abadi
To achieve our aim to find MTDLs for Alzheimer’s disease, all compounds were tested against human AChE as shown in Tables 1–4. The compounds were tested at 10 µM screening concentration then IC50 values were determined for compounds showing higher than 50% inhibition at 10 μM. Similar to the activity towards H3R, pyrrolidine derivatives were among the most potent compounds against AChE regardless of the spacer length. All compounds having pyrrolidine showed % inhibition of more than 50% at 10 µM, however, the strongest inhibitor was found to be compound 3b bearing the 2 methylene groups with an IC50 value of 0.44 µM. Interestingly, and unlike what was observed towards H3R, the 2nd best pyrrolidine derivative is compound 3n with 4-carbon spacer (IC50 = 1.3 µM), indicating that spacer length of two and four methylene groups (Table 2 and Figure 2) was generally superior for AChE inhibition.
Modulation of SETDB1 activity by APQ ameliorates heterochromatin condensation, motor function, and neuropathology in a Huntington’s disease mouse model
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Yu Jin Hwang, Seung Jae Hyeon, Younghee Kim, Sungsu Lim, Min Young Lee, Jieun Kim, Ashwini M. Londhe, Lizaveta Gotina, Yunha Kim, Ae Nim Pae, Yong Seo Cho, Jihye Seong, Hyemyung Seo, Yun Kyung Kim, Hyunah Choo, Hoon Ryu, Sun-Joon Min
After adding 5-(allyloxy)-2-chloroquinoline 3 (33 mg, 0.15 mmol) to a vial, pyrrolidine (190 µl, 2.28 mmol) was slowly added. The reaction mixture was stirred at 140 °C for 12 h. After confirming the termination of reaction by TLC, H2O was slowly added. The reaction mixture was separated into an ethyl acetate layer and an H2O layer using a separatory funnel. After drying the organic layer with anhydrous MgSO4, the solvent was removed by vacuum distillation. The mixture was purified by column chromatography on silica gel (ethyl acetate/hexane = 1:4) to obtain the target compound 4 (white solid, 29 mg, 76%). 1H NMR (CDCl3, 400 MHz) δ 8.30 (d, J = 9.2 Hz, 1H), 7.39 (t, J = 8.1 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 6.67 (d, J = 9.2 Hz, 1H), 6.54 (d, J = 7.6 Hz, 1H), 6.20–6.10 (m, 1H), 5.49 (dd, J1=17.3 Hz, J2=1.6 Hz, 1H), 5.32 (dd, J1=10.5 Hz, J2=1.4 Hz, 1H), 4.66 (dd, J1=5.1 Hz, J2=1.4 Hz, 2H), 3.63–3.60 (m, 4H), 2.03–2.00 (m, 4H). 13C NMR (CDCl3, 100 MHz) δ 156.1, 154.5, 149.6, 133.5, 131.6, 129.2, 119.0, 117.3, 114.3, 108.9, 101.5, 68.9, 46.8, 25.6. GC/MS: m/z (EI) 254 (M+). HPLC purity: 98.74%.
Synthesis of thiazolidin-4-ones and thiazinan-4-ones from 1-(2-aminoethyl)pyrrolidine as acetylcholinesterase inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Adriana M. das Neves, Gabriele A. Berwaldt, Cinara T. Avila, Taís B. Goulart, Bruna C. Moreira, Taís P. Ferreira, Mayara S. P. Soares, Nathalia S. Pedra, Luiza Spohr, Anita A. A. dE Souza, Roselia M. Spanevello, Wilson Cunico
Previous studies also have evaluated the effects of the others thiazolidin-4-ones compounds on AChE activity. Özadalı et al.37 report the synthesis of thiazolidin-4-ones derived from different heterocyclic and showed that these compounds have higher antihistamine activity but not anticholinergic action. Other studies have reported that the presence of pyrrolidine heterocycle in the synthesised products showed a potential inhibitory effect of AChE38,39. In addition, previous research from our research group has demonstrated the synthesis of benzothiazinan-4-one and the potential of some compounds in inhibited the AChE activity from hippocampus and cerebral cortex from rats, demonstrating the importance of this heterocycle in the cholinergic action27. Comparing these reports with the study proposed in this paper, I point out that the union of thiazolidin-4-one and thiazinan-4-one with pyrrolidine heterocycle aimed at enhancing AChE inhibition activity, as indeed observed with the results found.