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Clinical Detection of Exposure to Chemical Warfare Agents *
Published in Brian J. Lukey, James A. Romano, Salem Harry, Chemical Warfare Agents, 2019
Benedict R. Capacio, J. Richard Smith, Robert C. diTargiani, M. Ross Pennington, Richard K. Gordon, Julian R. Haigh, John R. Barr, Brian J. Lukey, Daniel Noort
This chapter on medical diagnostics provides a basic outline and references for the state-of-the-art analytical methods presently available in the literature. First, we describe the collection, handling, storage, and shipping of biological samples for CWA analysis as well as sample submissions requiring a chain of custody. Then, we discuss specific agents: nerve agents, vesicants, cyanide, phosgene, and 3-quinuclidinyl benzilate.
Stimulus-Secretion Coupling: Receptors
Published in Stephen W. Carmichael, Susan L. Stoddard, The Adrenal Medulla 1986 - 1988, 2017
Stephen W. Carmichael, Susan L. Stoddard
Yamanaka, Kigoshi and Muramatsu (1986a) characterized muscarinic receptors in bovine adrenal medullary microsomes by using tritiated quinuclidinyl benzilate. They found that specific binding of the agonist to microsomes is rapid, reversible, saturable, and of high affinity. Whereas quinuclidinyl benzilate appeared to bind to a single class of sites, other muscarinic agonists (acetylcholine, carbamoylcholine, oxotremorine) appeared to occupy at least two sites. Apparently, the predominant site is the M1 muscarinic site. In a follow-up study, Yamanaka, Kigoshi and Muramatsu (1986b) found that copper enhanced the affinity of carbamoylcholine at the low-affinity binding site, with a slight increase in the affinity at the high-affinity binding site. On the other hand, copper slightly decreased the binding affinity of the antagonist pirenzepine and of atropine. They concluded that low concentrations of copper may modulate the muscarinic receptors in the adrenal medulla by selectively increasing agonist affinity.
Radiotracer Localization by Receptor-Ligand Interactions
Published in Lelio G. Colombetti, Principles of Radiopharmacology, 1979
Raymond E. Gibson, William C. Eckelman, Waclaw J. Rzeszotarski, Victor Jiang, J. Krijn Mazaitis, Chang Paik, Toru Komai, Richard C. Reba
Quinuclidinyl benzilate is a tertiary amine that has properties like atroprine, but a 10- to 100-fold higher affinity for the muscarinic receptor (Table 5). Because QNB is a tertiary amine it can cross the blood-brain barrier. It is a psychoactive compound, like atropine, but because of the higher affinity is much more potent and can be hazardous when handled in milligram quantities. The quaternary salt of QNB (3H- MQNB), on the other hand, cannot cross the blood-brain barrier and is quite innocuous. Preparations of the quaternary salt in Librax® are taken orally as an anticholinergic and antispasmodic.
Therapeutic approaches to cholinergic deficiency in Lewy body diseases
Published in Expert Review of Neurotherapeutics, 2020
Matthew J. Barrett, Leslie J. Cloud, Harsh Shah, Kathryn L. Holloway
There are five subtypes of muscarinic receptors (M1–M5). The M1, M4, and M5 receptors are predominantly expressed in the CNS. The M1 receptor is widely expressed in cortex and hippocampus and is implicated in learning and memory functions. It has received the greatest attention as a therapeutic target in dementia syndromes. The M2 and M3 receptors are expressed in the periphery and are responsible for vagally mediated cardiac functions (M2) and regulation of glandular secretion and smooth muscle contractility (M3) (reviewed by [88]). These peripheral muscarinic receptors are responsible for most of the dose-limiting side effects of muscarinic agonists. Early pathological studies found increased binding of [3H] quinuclidinyl benzilate (QNB), a ligand of M1/M4 receptors, in frontal lobes of PD brains compared to controls [89,90]. One of these studies found that the increase in frontal QNB binding was greater in PDD than PD and in those receiving anticholinergic medications [90]. Subsequent studies confirmed an increase in muscarinic receptors in Lewy body dementias. A pathological study of DLB found increased M1 receptor levels in the temporal lobe; M2 receptor binding was increased in frontal and temporal cortex in PD, and greater receptor density was associated with the degree of dementia [91]. Another DLB study found an increase in M1 receptors in temporal and parietal cortex, and delusions were associated with increased M1 receptors in Brodmann area 36 in temporal lobe [92]. Nuclear imaging studies using muscarinic receptor ligands in PD report increased binding in frontal lobe in PD and additional increased binding in occipital lobe in PDD (reviewed by [93]). The most often proposed explanation for the overall increased muscarinic receptor density in Lewy body diseases is compensatory upregulation in response to reduced cholinergic input [91,93].
In vitro investigating of anticancer activity of new 7-MEOTA-tacrine heterodimers
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Jana Janockova, Jan Korabecny, Jana Plsikova, Katerina Babkova, Eva Konkolova, Dana Kucerova, Jana Vargova, Jan Koval, Rastislav Jendzelovsky, Peter Fedorocko, Jana Kasparkova, Viktor Brabec, Jan Rosocha, Ondrej Soukup, Slavka Hamulakova, Kamil Kuca, Maria Kozurkova
THA is currently used as a versatile scaffold in medicinal chemistry for designing novel hybrid compounds with improved pharmacological and toxicological profiles affecting several pathological mechanisms, e.g. in Alzheimer’s disease pathophysiology14–18. The THA derivative 7-MEOTA (7‐methoxy‐1,2,3,4‐tetrahydroacridin‐9‐amine, Figure 1), which was developed in our laboratory and primarily tested to antagonize anticholinergic syndrome evoked by scopolamine, ditrane and 3-quinuclidinyl benzilate19,20 and also as a prophylactic agent against organophosphate poisoning21, displayed a better toxicological profile than THA5. Mansouri et al.22 examined the mechanism of mitochondrial function damage during treatment with THA. Based on the chemical structure, it was postulated that THA might have a similar mechanism of action as the antitumor agent acridine (Figure 1) and related derivatives (e.g. mAMSA, imidazoacridinones, bis-tacrine, Figure 1)22. These acridines are able to intercalate between the planar bases of DNA and to inhibit nuclear type II topoisomerase (Topo II)23–26. In addition, a variety of bis-acridines have been developed with anticancer activity27,28. Further research also revealed that THA derivatives might be engaged also in interaction with type I topoisomerase (Topo I)29. THA itself was found to be a relatively weak catalytic inhibitor of Topo II implying inhibition of DNA synthesis. The latter led to depletion of mitochondrial DNA and ultimately to apoptosis22,29. Topo I and II are nuclear enzymes which play an important role by formatting superhelical DNA structures and thus ensuring essential cell functions. The topology of DNA can be regulated by certain enzymes leading to mutual transformation of its topological isomers and to the successive relaxation. Catalytic activity of topoisomerases lies in introduction DNA of single (Topo I) or double (Topo II) strand breaks. More recently, topoisomerases emerged as target of great interest in the development of novel antibacterial and anticancer drugs30,31.