Muscarinic receptors differentiation

Differential effects of the allosteric modulator alcuronium on various probes for the m2 muscarinic receptor. 

Roeske WR, Venter JC. The differential loss of [3H]pirenzepine vs [3H] (-)-quinuclidinylbenzilate binding to soluble rat brain muscarinic receptors indicates that pirenzepine binds to an allosteric state of the muscarinic receptor. Biochem Biophys Res Commun 1984 118 950-957. 

EEG slow waves. The differential EEG and ACh responses to dialysis delivery of AF-DX 116 (M2/M4) versus pirenzepine (M1/M4) supports the conclusion that, in B6 mouse, postsynaptic muscarinic receptors of the Ml subtype form one receptor mechanism by which ACh activates the EEG (Douglas et al, 2002a). The data summarized in Fig. 5.11 provide direct measures of G protein activation in basal forebrain and prefrontal cortex by muscarinic cholinergic receptors (DeMarco et al, 2004). The in vitro data of Fig. 5.11A indicate the presence of functional muscarinic receptors in regions of B6 mouse prefrontal cortex where in vivo microdialysis studies (Douglas et al, 2002a, b) revealed modulation of ACh release and EEG by pre- and postsynaptic muscarinic receptors (Figs. 5.9 and 5.10). 

Costa LG, Schwab BW, Murphy SD. 1982a. Differential alterations of cholinergic muscarinic receptors during chronic and acute tolerance to organophosphorus insecticides. Biochem Pharmacol 31 3407- 3413. 

Granon S, Poucet B, Thinus-Blanc C, Changeux JP, Vidal C. (1995). Nicotinic and muscarinic receptors in the rat prefrontal cortex differential roles in working memory, response selection, and effortful processing. Psychopharmacoiogy (Berlin). 119(2) 139-44. 

Hou, Y., Chang, V., Capper, A. B., Taussig, R., and Gautam, N. (2001). G protein [I subunit types differentially interact with a muscarinic receptor but not adenylyl cyclase type II or phospholipase G-/12/3. / Biol. Chem. 276, 19982-19988. 

Bannister RA, Melliti K, Adams BA (2004) Differential modulation of CaV2.3 Ca2+ channels by Galphaq/11-coupled muscarinic receptors. Mol Pharmacol 65 381-8 Barclay JW, Craig TJ, Fisher RJ et al (2003) Phosphorylation of Muncl8 by protein kinase C regulates the kinetics of exocytosis. J Biol Chem 278 10538—45 Barrie AP, Nicholls DG, Sanchez-Prieto J et al (1991) An ion channel locus for the protein kinase C potentiation of transmitter glutamate release from guinea pig cerebrocortical synaptosomes. J Neurochem 57 1398-1404... 

TABLE 4.1 Differential Effects of the Allosteric Modulator Alcuronium on Various Probes for the m2 Muscarinic Receptor... 

M2 receptor antagonists may also be used for the treatment of Alzheimer s disease, furthermore in the therapy of supraventricular bradycardia and for quantifying M2 receptors in the CNS with PET imaging. In the search for antagonists which clearly differentiate M2 from other muscarinic receptors, we investigated the two enantiomers of the widely used Hj-anti-histaminic drug dimethindene. (S)-Dimethindene proved to be a potent M2-selective antagonist with lower affinities for the Mj, M3 and M4 receptors. In addition, the (S)-enantiomer... 

Melchiorre, C., Cassinelli, A., Quaglia, W 1987. Differential blockade of muscarinic receptor subtypes by polymethylene tetraamines. Novel class of selective antagonists of cardiac M-2 muscarinic receptors. J. Med. Chem. 30, 201-204. 

The last two compounds that we tested, SS 62, CH3I and SS 63, CH3I (Fig. 2), have been shown to differentiate clearly between guinea pig atrium and guinea pig ileum when tested in functional experiments, but when they were tested on cell lines stably transfected with muscarinic receptors they completely lost their selectivity (Angeli et al., 1993). The affinity we found for our split chimeric M2-trunc/M3-tail receptor was intermediate between those found for Mj and M3 (Table 1). 

The 3H-labeled muscarinic oxotremorine, which is an experimental research compound, has also been shown to bind differentially to what may be subclasses of muscarinic receptor populations. 

Abdallah, E.A., Jett, D.A., Eldefrawi, M.E., and Eldefrawi, A.T., Differential effects of paraoxon on the M3 muscarinic receptor and its effector system in rat submaxUlary gland cells, J. Biochem. Toxicol, 7, 125, 1992. 

Jett, D. A., Fernando, J. C. Eldefrawi, M. E., and Eldefrawi, A. T. (1994). Differential regulation of muscarinic receptor subtypes in rat brain regions by repeated injections of parathion. To-xicol. l tl. 73, 33-41,... 

Chaudhuri, J Chakraborti, T, K., Chanda, S., and Pope. C. N, (199,3). Differential modulation of organophosphate-scn.sitive muscarinic receptors in rat brain by paraihion and chlorpyrifos. J. Biochem. Toxical. 8, 207-216. 

Van Den Beukel, I., Dijeks, F. A.. Vanderheyden, P, Vauquelin, G and Oortgiesen, M. (1997). Differential muscarinic receptor binding of acetylcholinc.stcra.se inhibitors in rat brain, human brain and Chirtese hamster ovary cells expre.ssing human receptors. J. Pharmacol. Exp. Then 281, 1113-1119. 

Leader H, Wolfe AD, Chiang PK, Gordon RK (2002) Pyridophens binary pyridostigmine-aprophen prodrugs with differential inhibition of acetylcholinesterase, butyrylcholinesterase, and muscarinic receptors. J Med Chem 45(4) 902-910. doi 10.1021/jm010196t... 

With respect to other ethnic groups, African Americans may have a differential sensitivity to weight gain on clozapine (de Leon etal, 2007). They may also require lower doses than Caucasians (Kelly et al, 2006) and inter-individual as well as ethnic responsiveness maybe partly explained by differences in dopamine receptor polymorphisms (Hwang et al, 2005). It is conceivable that side effects may also be differentially expressed based on pharmacodynamic differences resulting from polymorphisms in other receptor types (histaminergic, muscarinic, etc.). This area remains largely unexplored with respect to ethnic differences in antipsychotic side effects. 

Pals-Rylaarsdam, R., and Hosey, M. M. (1997) Two homologous phosphorylation domains differentially contribute to desensitization and internalization of the m2 muscarinic acetylcholine receptor. J. Biol. Chem. 272, 14152-14158. 

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