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A Brief Background
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
Organic reactions are used to synthesise drugs. Considerations of the stereochemistry are obviously vital in the design of new medicines. In cases where one of the two stereoisomers is the active drug, an asymmetric synthesis is required where special measures are taken to ensure stereospecificity. With knowledge of the characteristic reactions that different functional groups display, organic chemists can synthesise a target drug molecule from the relevant readily available starting materials. To build a target molecule, making carbon-carbon bonds is essential. Functional groups that will undergo addition reactions are useful for this purpose. To ensure strong interactions with the drugs’ biological target, a particular functional group may be needed in the molecule. Here, a substitution reaction may be relevant. Ultimately, a drug molecule is made with the correct size, shape, correctly positioned functional groups, and chemical properties that will interact with the biological system to produce a biological response. A selection of functional groups that are key to organic synthesis are shown in Figure 1.2. Whether the compound acts as a medicine or a poison depends on the dose level of the compound. This can be described by the drugs therapeutic index, which is a measure of a drugs beneficial effect at low dose versus its harmful effects at high dose. No drug is absolutely harmless and drugs may vary in the side effects they have.
Structures of benzodiazepine recognition site ligands
Published in Adam Doble, Ian L Martin, David Nutt, Calming the Brain: Benzodiazepines and related drugs from laboratory to clinic, 2020
Adam Doble, Ian L Martin, David Nutt
The majority of the benzodiazepines have no chiral centre; however, the seven-membered ring B can adopt one of two energetically preferred boat conformations; the molecule is thus termed pro-chiral. The methylene group at the 3-position of a 1,4-benzodiazepine ring is known to be either above or below the plane of the fused benzene ring, imparting conformational chirality to the molecule. It was originally thought that this puckering of the seven-membered ring placed the carbonyl oxygen atom on the same side of the molecule as the methylene carbon atom (Fryer, 1983). It was later shown, after examining many X-ray structures, that this proton-accepting oxygen atom can exist either above or below the plane of the A ring to an extent of approximately ± 0.5Å. In order to elucidate the stereospecificity of the receptor interaction several enantiomeric pairs with a chiral centre at position 3 have been prepared (Haefely et al, 1985). The introduction of a methyl substituent at this position leads to stabilisation of the conformation of the seven-membered ring. Both nuclear magnetic resonance (Sunjic et al, 1979) and X-ray crystallographic studies (Blount et al, 1983) are consistent with the suggestion that the conformation of ring B, responsible for high affinity interaction with the receptor, is that shown for diazepam in Figure 5.3.
Localizing Drug and Neurotransmitter Receptors in Vivo with Tritium-Labeled Tracers
Published in William C. Eckelman, Lelio G. Colombetti, Receptor-Binding Radiotracers, 2019
Identification of receptors by binding techniques has proven tremendously beneficial for furthering our knowledge of receptors. In these many studies it has become apparent that one must exercise extreme caution in accepting a binding site as a receptor. First, there is the issue of receptor vs. nonreceptor binding. There have been several instances when a binding site having some properties normally associated with a receptor has been found to be unrelated to receptor. For example, in many studies it has been shown that various receptors show chemical stereospecificity. In early receptor-binding studies, stereospecificity was regarded as the hallmark criterion of receptor binding. However, in later studies it was shown that stereospecificity was not totally adequate as a hallmark feature for identifying receptor binding. Stereospecific binding of radioactive drugs has been described for even inert materials such as glass fiber filters.11 In addition, it has been shown that drugs bind to a multiplicity of receptors. While this issue is somewhat different from the receptors versus nonreceptor issue, it does relate to the critical issue of selectivity. For example, investigators originally thought spiperone was highly selective for dopamine receptors in brain.12,13 It has since been shown however that spiperone binds to both serotonin and noradrenergic alpha receptors as well.14,15 Thus, it is important to realize that one has to rule out various pitfalls and problems and that binding can occur both to nonreceptor sites as well as to multiple receptor sites.
Design, synthesis and characterization of enzyme-analogue-built polymer catalysts as artificial hydrolases
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Divya Mathew, Benny Thomas, Karakkattu Subrahmanian Devaky
Ohkubo et al. in 1996 reported the synthesis of another “water soluble esterase MIP” with the imprints of a racemic transition state analogue phenyl-1-benzyloxycarbonyl-3-methylpentyl phosphonate for the hydrolysis of p-nitrophenyl N-(benzyloxycarbonyl)-L/D-Leucinate (Z-L/D-Leu-PNP) [56] (Figure 19). The esterase mimic with L-histidine and quaternary trimethyl ammonium groups was synthesized by radical initiated polymerization of methyl-N-acryloyl-L-histidinate, acrylamide and N-(3-trimethylaminopropyl)acrylamide in presence of N,N-ethylene-bis-(2-propeneamide) as the crosslinker. The water-soluble esterase MIP exhibited 4.3 times rate enhancement over the solution reaction containing same concentration of histidine monomer. The esterase MIP accommodated Z-L-Leu-PNP in the substrate recognition site to form catalyst-substrate complex with −4 mol−1dm3. Thus, the reaction cavity was seemed to be predominantly recorded the shape of L-TSA and exhibited 3-fold substrate stereospecificity. Additionally, the water-soluble esterase MIP exhibited substrate shape-selectivity by recognizing both the skeletons of the N-benzyloxy (Z) group and the L-Leu side chain of the substrates. Further they presented the rac-TSA as the competitive inhibitor for Z-L-Leu-PNP.
Comparative toxicity and toxicokinetic studies of oxiracetam and (S)-oxiracetam in dogs
Published in Xenobiotica, 2019
Tian-tian Liu, Xin-miao Guo, Zu-yuan Rong, Xiang-feng Ye, Jin-feng Wei, Ai-ping Wang, Hong-tao Jin
As a consequence of the rapid advances in chiral synthesis and separation technologies, combined with new regulatory policies for chiral pharmaceuticals, chiral drugs have become an important focus for research and development of new molecular entities (Calcaterra & D'Acquarica, 2018; Nunez et al., 2009; Srinivas, 2004). Stereoisomers (enantiomers and diastereoisomers) not only differ from one another in their pharmacological effects, but also in their pharmacokinetic (adsorption, distribution, biotransformation, and excretion) profiles (Brocks, 2006; Hutt, 2007) and toxicological properties (Natarajan & Basak, 2011; Smith, 2009). Understanding the stereospecificity of in vitro and in vivo pharmacokinetics/toxicokinetics may assist in delineating the developmental path of the racemate and/or the pure enantiomers. The differential actions and toxicities determine enantiomer selection to maximize clinical effects or mitigate drug toxicity. Toxicological evaluation of chiral drugs, therefore, deserves increased attention.
Stereoselective pharmacokinetic and pharmacodynamic analysis of a CNS-active sulphamoylphenyl carbamate derivative
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
David Bibi, Bella Shusterman, Alessio Nocentini, Claudiu T. Supuran, Meir Bialer
The issue of drug chirality is a major theme in the design, discovery, and development of new active pharmaceutical entities due to the understanding of the role of stereospecificity and molecular recognition in drugs activity. Thus, most of the new chiral drugs reaching the market are single enantiomers, rather than racemic mixtures7. Enantiomers are often readily distinguished by biological systems and may have different pharmacokinetic (PK) or pharmacodynamic (PD) properties in their wanted (designated) indication or unwanted effects5,6.