Muscarinic subtypes

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. 

Acetylcholine receptors. There are numerous receptors for ACh (Fig. 12—10), of which the major subtypes are nicotinic and muscarinic subtypes of cholinergic receptors. Classically, muscarinic receptors are simulated by the mushroom alkaloid muscarine and nicotinic receptors by the tobacco alkaloid nicotine. Nictotinic receptors are all ligand-gated, rapid-onset, and excitatory ion channels, which are blocked by curare. Muscarinic receptors, by contrast, are G protein—linked, can be excitatory or inhib-... 

The naturally occurring drugs atropine and scopolamine have a different sort of antagonistic effect They block the muscarinic subtype of acetylcholine receptors. As a result, they impair our ability to form new memories and produce considerable mental confusion and drowsiness. At high doses, atropine and scopolamine can be lethal. 

The issue of drug selectivity is related closely to the fact that many receptor populations can be divided into various subtypes according to specific structural and functional differences between subgroups of the receptor. A primary example is the cholinergic (acetylcholine) receptor found on various tissues throughout the body. These receptors can be classified into two primary subtypes muscarinic and nicotinic. Acetylcholine will bind to either subtype, but drugs such as nicotine will bind preferentially to the nicotinic subtype, and muscarine (a toxin found in certain mushrooms) will bind preferentially to the muscarinic subtype. 

M5 AChR represent the predominant muscarinic subtype in dopamine-containing neurons of the pars compacta of the substantia nigra and the ventral tegmental area. 

Answer A. ACh receptors in the CNS are present on less than 5% of the neuronal population. Most of them are of the muscarinic subtype, M (excitatory) and M2 (inhibitory), via G-protein coupled changes in cAMP. Nicotinic receptors are excitatory via direct coupling to cation channels (Na/K), and their activation does not initiate second messenger pathways. Other CNS transmitter receptors that are directly coupled to ion channels include those for GABA and glutamic add. Almost all CNS receptors for DA, NE, 5HT, and opioid peptides are coupled to ion channels via second messenger systems. 

The pattern of cholinergic receptor sites in PC is similar to the efferent inputs of HDB neurons. An array of anatomical techniques show all four muscarinic subtypes (m, mj, m3, and m4) to be present in layer II PC (Buckley et al. 1988 Spencer et al. 1986 Zilles et al. 1989 and Rotter et al. 1979). The m, receptor subtype has also been identified immunocytochemically to be on dendritic spines in layer I, but the identification of these... 

Tetraamines were shown to be competitive antagonists of muscarinic receptors. Melchiorre et al. (1987) presented in J. Med. Chem. the most potent and cardioselective compound of this class, methoctramine (Fig. 2), displaying a selectivity ratio (atria vs. ileum or bladder) of ca. 270. TIPS (1989) showed a picture of muscarinic receptor nomenclature recommended by the Fourth International Symposium on Subtypes of Muscarinic Receptors (Wiesbaden, 1989) where three pharmacologically defined muscarinic subtypes (M1-M3) and five cloned muscarinic subtypes are placed side by side. Among the selective antagonists showed in this classification, p-fluorohexa-hydrosila-difenidol appears (Lambrecht et al., 1989) as a new Mj-selective compound (Fig. 2). In the aforementioned Symposium, Eberlein et al. (1989) presented AF-DX 384 (Fig. 2), a successor of AF-DX 116. 

Classical muscarinic agonists selectivity for M2 vs. M[ muscarinic subtypes... 

Watson, M. et ah, 1986. pH]Pirenzepine and (-)-[ H]quinuclidinyl benzilate binding to rat cerebral cortical and cardiac muscarinic cholinergic sites I. Characterization and regulation of agonist binding to putative muscarinic subtypes. J. Pharmacol. Exp. Ther. 237, 411-418. 

Acetylcholine neurotransmission was found to play an essential role in memory function, Alzheimer s disease and parkinsonism. This has added a new (CNS) dimension to the therapeutic portfolio of cholinergic drugs, specifically muscarinic agents, as muscarinic subtype receptors are predominant in the CNS. ... 

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