Adrenergic Agonists
Sahab Uddin, Rashid Mamunur in Advances in Neuropharmacology, 2020
Dobutamine interacts with β and α receptors and was earlier thought being a selective β1 receptor agonist. It is similar in structure to dopamine. Both enantiomeric forms exist as a racemic mixture. The levo (−) isomer is an α1 receptor agonist while the dextro (+) isomer is an antagonist of α1 receptors. Both isomers have agonist effects on beta receptors although dextro isomer is more potent. Dobutamine produces more inotropic effects binding to the α1 receptors than the chronotropic effects on the heart. Cardiac output rises and then there is a change in the peripheral resistance. In some of the patients, there might be a significant increase in the heart rate and blood pressure and long-term effect is unclear. There might be a chance to develop tolerance. Dobutamine is used for a short-term period for treating decompensation of heart which happens in congestive heart failure or MI or after heart surgery. The onset of activity is fast, within 1–10 min and has a 2-min half-life (Brunton et al., 2011; Golan, 2012; Stevens et al., 2008). It penetrates well into CNS because of the absence of catechol in structure. Metabolism happens in the tissues and in the liver. The plasma half-life of the drug is approximately 2 min and excreted via urine (Rataboli, 2010; Florey, 2008).
Paper 4 Answers
James Day, Amy Thomson, Tamsin McAllister, Nawal Bahal in Get Through, 2014
Stereoisomerism is the existence of molecules with the same chemical constituents but different spatial arrangements. Geometric and optical are two forms of stereoisomerism. In optical stereoisomerism a chiral centre exists. This is either a carbon atom or a quaternary nitrogen atom. They have four bonds, with a different chemical group connected to each. This allows different arrangements of the chemical groups to the chiral centre. This produces molecules that are mirror images of each other and cannot be superimposed on each other. These mirror images are termed enantiomers. When prepared pharmaceutically, mixtures of these enantiomers are produced in equal proportions. This is termed a racemic mixture. Examples of drugs that are produced as racemic mixtures are the volatile anaesthetics (except sevoflurane), bupivacaine and atropine. Propofol and sevoflurane do not contain a chiral centre so have no enantiomers.
Determination of Toxicity
David Woolley, Adam Woolley in Practical Toxicology, 2017
The presence of enantiomers of a molecule can also affect toxicity or action, as they may be associated with different effects, either in degree or type; for example, thalidomide has two enantiomers, only one of which was associated with the characteristic developmental toxicity. For this reason, it is sometimes advisable to develop only one of the enantiomers; in fact, this may well be the preferred strategy of the regulatory authorities. Development of the racemic mixture may be acceptable, if there is rapid conversion between the two forms in vivo, making distinction between them impossible. One final point to consider is that the International Conference on Harmonisation (ICH) M7 guideline requires that all starting products, intermediates, by-products, and impurities in pharmaceutical products must undergo evaluation for bacterial mutagenicity and be controlled below a threshold. The mutagenic evaluation can be either via literature review or by in silico analysis using a rule-based and statistical structural activity relationship program–if both systems indicate a negative result, no further action is required. If a substance is predicted to be mutagenic, it should be assayed for bacterial mutagenicity or controlled below a threshold.
Pharmacokinetics and pharmacodynamics of dextromethorphan: clinical and forensic aspects
Published in Drug Metabolism Reviews, 2020
Ana Rita Silva, Ricardo Jorge Dinis-Oliveira
Therefore, DXM is chemically an opium alkaloid derivative but since it does not act pharmacologically at opioid receptors, it is not an opioid and does not have analgesic, euphoriant, and respiratory depression effects, such as codeine and morphine (Bem and Peck 1992; Jasinski 2000; Pechnick and Poland 2004). In other words, DXM and DXO, both dextrorotatory enantiomers, are non-opioid opium alkaloid derivatives. Racemethorphan is the racemic mixture composed by the two enantiomers DXM and levomethorphan (Wong and Sunshine 1996). Racemorphan or morphanol refers to the racemic mixture of DXO and levorphanol, both with pharmacological and toxicological effects similar to their correspondent methyl ether derivatives (Aumatell and Wells 1993). This enantiomeric behavior is characteristic of other opioids. Indeed, dextrorotatory opioids have very different pharmacological profiles than their levorotatory isomers. Unlike the levorotatory opioids, dextrorotatory generally have little or no affinity to the mu (MOR; µ), delta (DOR; δ), or kappa (KOR; Κ) opioid receptors, and thus do not carry the same abuse and addiction potential as their levorotatory enantiomers (Sromek et al. 2014). Dextrorotatory enantiomers typically act as weak to moderate noncompetitive NMDA receptor antagonists and have affinity to the σ1 and α3β4 nicotinic receptors (Glick et al. 2001). Both dextrorotatory and levorotatory opioids have antitussive properties.
N-Methyl-D-Aspartate (NMDA) receptor modulators: a patent review (2015-present)
Published in Expert Opinion on Therapeutic Patents, 2020
Hazem Ahmed, Ahmed Haider, Simon M. Ametamey
The patent records the synthesis and the IC50 determination of the aforementioned classes of compounds. The binding affinity experiments were performed by employing two-electrode voltage clamp recordings using rat recombinant receptors expressed in Xenopus laevis oocytes. Extensive structure-activity relationship studies were performed and a compound designated 997–74 emerged as the most potent and selective GluN2C/GluN2D antagonist with selectivity values of 220 nM (GluN2A/GluN2D) and 138 nM (GluN2B/GluN2D). Furthermore, it was clearly indicated that the (S)-enantiomer is the preferred enantiomer, given the higher binding affinity and selectivity when compared to the corresponding (R)-enantiomer and the racemic mixture Figure 23. The inventors of the patent suggested modifications to the filed compounds since their potency and blood-brain barrier (BBB) penetration potential of the previously described work were not aligned; highly potent compounds exhibited low BBB penetration potential, and vice versa. The current patent, however, does not provide data regarding BBB penetration potential [189].
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
It has been more than twenty years since the discovery of oxiracetam (ORT, 4-hydroxy-2-oxo-1-pyrrolidine acetamide), a derivative of piracetam, which is a nootropic used for treating memory decline and various cognitive function disorders (Bottini et al., 1992; Mondadori et al., 1996; Nicholson, 1990; Villardita et al., 1992). Oxiracetam has also been associated with promising central nervous system protective effects, including in cerebrovascular impairment (Kometani et al., 1991), ischemic stroke(Wang et al., 2014), and brain injury(Yi et al., 2016). Recent studies have shown that oxiracetam can reduce cognitive injury at high altitude (Hu et al., 2017; Li et al., 2017) and was selected to be co-administered with nerve growth factor for the treatment of hypertensive cerebral hemorrhage (Sun et al., 2018). Oxiracetam has an asymmetric carbon, and its enantiomers are (S) -and (R)-ORT (Figure 1). It is used as a racemic mixture in clinical treatment. Studies have shown that (S)-ORT has high efficacy and is the active component of racemic oxiracetam (Fan et al., 2018; Li et al., 2017). To the best of our knowledge, most studies have focused on differences in the effects of ORT enantiomers from a pharmacological (Baumann & Eap, 2001; Kasprzyk-Hordern, 2010) or pharmacokinetic (Son et al., 2004; Wan et al., 2014; Zhang et al., 2015a) perspective. However, the in vivo toxicity and toxicokinetics of oral ORT and (S)-ORT have not yet been investigated. Accordingly, ORT and (S)-ORT were evaluated in acute and 90-day repeated-dose toxicity and toxicokinetic studies in dogs following oral exposure, as described herein.
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