Muscarinic cholinergic receptors selective agonists

Cholinergic receptors Receptors for acetylcholine are classified into muscarinic (muscarine is a selective agonist) and nicotinic (nicotine is a selective agonist). There are five muscarinic (mj to m5) and two nicotinic (neuronal, or ganglionic, and skeletal muscular) subtypes. 

Acetylcholine (9.12) binds both types of cholinergic receptors muscarinic and nicotinic (Figure 9.9). The names of these receptor types were based on muscarine (9.13) and nicotine (9.14), selective agonists for each receptor. A muscarinic response is characterized by nausea, salivation, and tearing. Nicotinic responses are noted by an acceleration of the heart rate. Acetylcholine s ability to elicit a response from both subtypes of receptors may imply that different conformations of acetylcholine may be responsible for binding to each receptor. 

Another example is the antidepressant minaprine (Fig. 5.14). In addition to reinforcing serotoninergic and dopaminergic transmission, this amino-pyridazine possesses weak affinity for muscarinic Mj receptors Ki = 17 (jlM). Simple chemical variations allow the dopaminergic and serotoninergic activities to be abolished, and the cholinergic activity up to nanomolar concentrations to be boosted.Similarly, chemical variations of the Dz/ D3 nonselective benzamide sulpiride (Fig. 5.15) led to compound Do 897, a selective and potent D3 receptor partial agonist. ... 

When designing a dmg to be a cholinergic agonist, selectivity is highly desirable but not a simple term, as therapeutic candidates should be selective for the cholinergic receptor among other neurological receptors, selective for nicotinic or muscarinic, or selective for spedfic subtypes or tissue types. Selectivity could be achieved on the pharmacodynamic level, where the stmcture of the dmg molecule makes it more active at one receptor than another, or on the pharmacokinetic level where the molecular stmcture of the dmg makes it more available to spedfic tissues. Equally important, the new stmcture should retain ACh s activity (see Box 16.1). 

Cholinergic antagonists have a larger therapeutie role than agonists. Again, we can distinguish drugs that selectively affect nicotinic and muscarinic receptors. 

Relief from pain. Selected cholinergic agents have been found that display antinociceptive (analgesic) effects grossly similar to those of morphine. Most of these are nicotinic receptor agonists, but a modest number of muscarinic agonists have been found that also display antinociceptive effects. 

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