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Cholinergic Antagonists
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Vishal S. Gulecha, Manoj S. Mahajan, Aman Upaganlawar, Abdulla Sherikar, Chandrashekhar Upasani
Atropine is found with hyoscyamine in A. belladonna. Hyoscyamine readily hydrolyzes to atropine in aqueous alcohol. Therefore, atro-pine is a naturally occurring alkaloid in the form of a racemic mixture of d- and l-hyoscyamine in equal parts (Finar, 1965). It was found that upon hydrolysis, atropine gave (±)-tropic acid (C9H10O3) and tropine (C8H15ON), which was shown to be alcohol. The presence of hydroxyl group in the structure of tropine makes it a saturated compound. On the other hand, dicarboxylic acid derivative of tropine, the tropinic acid contains the same number of carbon atoms as that of tropine (Rang and Dale, 2007; Shrivastava, 2017).
Antagonists at Muscarinic Cholinergic Receptors
Published in Kenneth J. Broadley, Autonomic Pharmacology, 2017
(−)-Hyoscine (scopolamine) is the ester of tropic acid and scopine, the latter differing from tropine by the addition of an oxygen bridge (Table 9.1). The potency of hyoscine is equivalent to that of atropine, having pA2 values of 9.5 and 9.0, respectively, for antagonism of the contractile responses of guinea-pig ileum to Ach (Bowman & Rand 1980). It is almost completely metabolized in the liver. The quaternary derivative, N-methylscopolamine, is a potent antagonist with no selectivity between muscarinic receptor subtypes. It is widely used as [3H]N-methylscopolamine ([3H]NMS) for radioligand binding to the low affinity state of the muscarinic receptor. Homatropine is the semisynthetic ester of tropine and mandelic acid (Table 9.1) which has approximately one tenth of the muscarinic blocking potency of (−)-hyoscyamine. The addition of an N-methyl quaternizing group to homatropine increases muscarinic activity three-fold and nicotinic ganglionic blocking activity 10-fold.
Antiemetics and Cancer Chemotherapy
Published in John Kucharczyk, David J. Stewart, Alan D. Miller, Nausea and Vomiting: Recent Research and Clinical Advances, 2017
Several recent trials have also documented that high dose bolus metoclopramide may be a less effective antiemetic than earlier studies had suggested. As noted previously, a study by Roemeling et al.13 of high dose metoclopramide therapy in patients receiving cisplatin and doxorubicin found that the circadian timing of cisplatin administration appeared to be the major determinant of the frequency of vomiting, not the dose of metoclopramide administered. The toxicity associated with metoclopramide therapy is an extension of its pharmacological action. Side effects include sedation, diarrhea, and extrapyramidal toxicity. A high incidence of extrapyramidal effects, especially akathisia, has been reported in up to 30% of patients.15 These extrapyramidal effects occur more frequently in young males. As in the case of phenothiazines, the prophylactic use of diphenhydramine or benz-tropine is usually effective. Symptoms such as akathisia may have a subtle onset. Drug-induced restlessness in such patients may be misinterpreted as being due to anxiety. It is important to recognize such extrapyramidal side effects early since they are preventable and may cause patients to refuse further treatments.
Pharmacological evaluation of Ashwagandha highlighting its healthcare claims, safety, and toxicity aspects
Published in Journal of Dietary Supplements, 2021
Deepa S. Mandlik (Ingawale), Ajay G. Namdeo
Withanolides is a group of steroidal lactones responsible for the pharmacological activity of roots of W. somnifera (Figure 2) (Budhiraja and Sudhir 1987). Laboratory investigations has concluded that over 35 phytoconstituents are present in the roots of W. somnifera (Rastogi and Mehrotra 1998). Phytochemical analysis has discovered the occurrence of diverse chemical constituents in different parts of W. somnifera. Up till now, more than 40 withanolides, 12 alkaloids, and rare sitoindosides have been present in the plant (Mirjalili et al. 2009) (Table 3). The most remarkable ingredients are tropine alkaloids such as Convolamine, Convoline, Convolidine, Convolvine, confoline, convosine, etc. (Prasad et al. 1974; Lounasmaa 1988; Singh and Bhandari 2000). The fresh plant of W. somnifera contains Fatty acids, Fatty alcohols, Volatile oils, Myristic acid, Palmitic acid, Linoleic acid, and Hextriacontane. The roots of W. somnifera contains Reducing sugar, Starch, Glycosides, and Withaniol acid. It also contains eight bases such as Withanine, Withananine, Withananinine, Pseudowithanine, Withasomnine, Somniferine, Somniferinine, and Somnine (Majumdar 1955; Maheshwari 1989; Mishra 1989).
Pharmacogenomics of drugs used to treat brain disorders
Published in Expert Review of Precision Medicine and Drug Development, 2020
Antiparkinsonian drugs are associated with the PGx activity of less than 50 genes, thus far. Different categories of antiparkinsonian drugs (anticholinergics, antihistamine ethers, tropine ethers, dopamine precursors and of donors of dopamine precursors, adamantanes, dopamine agonists, MAO-B inhibitors, COMT inhibitors) are substrates and/or inhibitors of 33 and 18 enzyme/protein gene products, respectively (inducers have not been identified so far), and are transported by 3 transporters (Table 2; Figure 6). CYP enzymes participate in the metabolism of 87% of drugs of these pharmacological categories. Antiparkinsonian drugs are major substrates of CYP3A4, CYP2C19, CYP2D6 and CYP2B6 (85%), CYP1A2 (82%), CYP3A5 (81%), UGT1A1 (69%), and UGT1A9 (68%); 38% are inhibitors of CYP3A4, 32% of CYP1A2, 25% of CYP2D6 and CYP2C19, 18% of CYP2C9, and 12% of CYP2A6 and CYP2E1. SLC22A1 (69%), SLC6A3 (63%), and ABCB1 (7%) are major transporters of most dopaminergic enhancers. Selegiline and Entacapone are associated with 47 pharmagenes, Tolcapone with 43, and L-DOPA with 36 [8, 9].
Optimisation of novel 4, 8-disubstituted dihydropyrimido[5,4-b][1,4]oxazine derivatives as potent GPR 119 agonists
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Yuanying Fang, Shaokun Zhang, Min Li, Lijuan Xiong, Liangxing Tu, Saisai Xie, Yi Jin, Yanhua Liu, Zunhua Yang, Ronghua Liu
In summary, we have designed, synthesised and biologically evaluated a series of novel pyrimido[5,4-b][1,4]oxazine derivatives as potent GPR119 agonists. In vitro, half derivatives exhibited strong EC50 values (<100 nM). Among the aliphatic amine moieties of this scaffold, the compound 10 with tropine amine ring displayed much more potent agonistic activity than piperidine amine and other rigid bicyclic amines. In the further optimisation of N-substitution, only isopropyl carbamate of tropine ring 15 improved the EC50 values and showed the greatest inherent activity. Accordingly, compounds 10 and 15 were conducted the oGTT in C57BL/6N mice. Both two agonists demonstrated blood glucose reduction effect in a dose-dependent manner. Furthermore, the optimised compound 15 was exerted improved 23.4% reduction in blood glucose AUC0–2h at the dose of 30 mg/kg comparing with Vildagliptin (17.9% reduction). Follow-up studies and their results will be reported in due course.