Muscarinic ligands

E.M. Jagoda, D.O. Kiesewetter, K. Shimoji, L. Ravasi, M. Yamada, J. Gomeza, J. Wess, W.C. Eckelman, Regional brain uptake of the muscarinic ligand, [ F]FP-TZTP, is greatly decreased in M2 receptor knockout mice but not in Ml, M3 and M4 receptor knockout mice. Neuropharmacology 44 (2003) 653-661. 

Snake toxins are potent (irreversible) muscarinic ligands... 

Heterocycles as selective muscarine ligands recognizing choline receptors 92KFZ(1)4. 

Direct coupling of a G protein to the heart K+ channel activated by muscarinic ligands was demonstrated in a cell-free system using inside-out patches. Addition to the bath (the cytoplasmic face of the patch) of GTPyS leads, after a lag, to permanent activation of K+ channels [144]. Similarly, addition of purified PTX-sensi-tive G protein from human erythrocytes (referred to originally as Gj ) or its a subunit complexed with GTPy and free of /3y subunits, also stimulates these channels, provided the G protein is preactivated by GTPyS [145]. These results defined the existence of a Gk and identified it physically as an ajSy heterotrimer and a PTX substrate. 

The lack of selective muscarinic receptor ligands has for a long time limited the definition of therapeutic treatment based on muscarinic receptors as targets. Some muscarinic ligands such as cev-imeline or xanomeline have been developed for the treatment of AD and other CNS disorders. Some muscarinic agonists (vedaclidine) have analgesic effects comparable to those produced by morphine or opiates [194],... 

FIGURE 15.28 Muscarinic ligands derived from the ester bio-isoster replacement of arecoline 12 and quinuclidine methyl ester 13. 

The functional Mi-selective agonist McN-A-343 (Figure 1) has been used in our laboratory as a starting point for the design of CNS-active muscarinic ligands, the primary objective being... 

Subsequent developments suggested that the effects of muscarinic receptor stimulation are mediated by second messengers that are biosynthesized by at least two important events 1) inhibition of adenylyl cyclase, and 2) activation of phospholipase C. Both involve a guanosine triphosphate (GTP)-dependent mechanism. Two other important developments were the synthesis of radiolabeled muscarinic ligands and the utilization of molecular biology techniques in the study of muscarinic receptors. 

Development of benzylpiperazines as subtype selective muscarinic ligands. 

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