Muscarinic receptors selective

Binding to, and irreversible inhibition of, muscarinic receptors (selectively M3 compared with Mj) was observed with some iV-(chloro- or bromoethyl)piperidines, and shown by kinetic studies of their hydrolysis, to be related to the intermediate azoniaspiro[2,5]octanes (Scheme 17) <92MI 840-01, 93MI 840-02>. The aziridinium ion is the most potent compared with the parent piperidines or with the alcohol (143). 

Anatoxin-a is the most potent and most stereospecific nicotinic acetylcholine receptor agonist thus far identified. It is also highly selective for nicotinic receptors over muscarinic receptors. The molecular parameters which influence the binding affinity, channel activation, channel blockade, and receptor desensitization are being studied. Modifications of the carbonyl and amine moieties can reduce or nearly eliminate the receptor agonist potency of the compounds and also determine the channel blocking characteristics. 

The debut of the selective AChR agonist (+)-anatoxin-a has provided a new tool for AChR physiology and pharmacology. (+)-Anatoxin not only has high affinity for the nicotinic AChR but it also has high selectivity for nicotinic over muscarinic receptors in the mammalian CNS. Recently, the use of (+)-anatoxin-a was essential to the identification of nicotinic receptors on cultured neurons (4), We are studying the features which allow it to bind with high affinity to the peripheral and central nicotinic receptors and the kinetic effects on receptor conformational... 

Eglen, RM and Watson, N (1996) Selective muscarinic receptor agonists and antagonists. Pharmacol. Toxicol. 78 59-78. 

Wall, SJ, Yasada, RP, Hory, F, Flagg, S, Martin, BM, Ginns, El and Wolfe, BB (1991) Production of antisera selective for Mi muscarinic receptors using fusion proteins distribution of Ml receptors in rat brain. Mol. Pharmacol. 39 643-649. 

The first and best-studied allosteric site on GPCRs is that on the muscarinic receptor [9,10,12,19,20]. For the five subtypes of these receptors that have been cloned and pharmacologically defined as Mi to M5, various agents have been identified that allosterically regulate selectively these... 

A growing number of other diverse compounds have also been shown to bind to an allosteric site on the muscarinic receptors. Among them are pirenzepine (highly selective for Mi receptor), lidocaine and verapamil (ion channel blockers), tacrine (anticholinesterase compound), batrachotoxin, and strychnine (glycine receptor antagonist) [25,31-35],... 

Birdsall NJ, Farries T, Gharagozloo P, Kobayashi S, Lazareno S, Sugimoto M. Subtype-selective positive cooperative interactions between brucine analogs and acetylcholine at muscarinic receptors functional studies. Mol Pharmacol 1999 55 778-786. 

An example of an irreversible antagonist with a very long action (usually many hours) is phenoxybenzamine, which blocks a-adrenoceptors and, less potently, H,-histamine and muscarinic receptors. Its structure is shown below. Also illustrated is benzilylcholine mustard, a highly active and selective irreversible blocker of muscarinic receptors. 

Bielarczyk H, Tomsig JL, Suszkiw JB. 1994. Perinatal low-level lead exposure and the hippocampal cholinergic system selective reduction of muscarinic receptor and cholineacetyltransferase in the rat septum. Brain Res 643 211-217. 

Imeri, L., Bianchi, S., Angeli, P. Mancia, M. (1994). Selective blockade of different brain stem muscarinic receptor subtypes effects on the sleep-wake cycle. Brain Res. 636, 68-72. 

Jacobson, K.A. et al. (1995) Molecular probes for muscarinic receptors Functionalized congeners of selective muscarinic antagonists. Life Sci. 56(11/12), 823-830. 

FIGURE 11-3 Structure of compounds important to the classification of receptor subtypes at cholinergic synapses. Compounds are subdivided as nicotinic (N) and muscarinic (Ad). The compounds interacting with nicotinic receptors are subdivided further according to whether they are neuromuscular (N,) or ganglionic (N2). Compounds with muscarinic subtype selectivity (M M2, M3, M4) are also noted. 

Thus, cholinergic receptor classification can be considered in terms of three stages of development. Initially, Dale [2] distinguished nicotinic and muscarinic receptor subtypes with crude alkaloids. Then, chemical synthesis and structure-activity relationships clearly revealed that nicotinic and muscarinic receptors were heterogeneous, but chemical selectivity could not come close to uncovering the true diversity of receptor subtypes. Lastly, analysis of subtypes came from molecular cloning, making possible the classification of receptors on the basis of primary structure (Fig. 11-2). 

The selectivity in muscarinic receptor coupling is not, however, absolute. Overexpression of receptors or of particular G proteins supports interactions that may differ from those described above. For example, M2 receptors expressed in Chinese hamster ovary cells not only inhibit adenylyl cyclase but also can stimulate phosphoinositide hydrolysis through a pertussis-toxin-sensitive G protein [52] this is not seen, however, when M2 receptors are expressed in Y1 cells. These findings indicate that caution must be exercised in interpreting data obtained when receptors are expressed, often at high levels, in cells in which they normally do not function. 

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. 

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