Nicotinic cholinergic agonist

Figure 5. Cartoon of a cholinergic synapse showing major steps in the synthesis of acetylcholine. The two major receptor types, the ionotropic nicotinic receptor and the metabotropic muscarinic receptor, are shown (see also Chapter 1). Presynaptic muscarinic (M2) and nicotinic receptors are also depicted. Drugs which have been widely used to manipulate the cholinergic systems, and which are mentioned in the text, include the muscarinic receptor antagonists scopolamine and atropine and the nicotinic receptor agonist nicotine. Anticholinesterases (discussed elsewhere in this volume) include drugs such as physostigmine, rivastigmine, donepezil, and galanthamine.

Increased stimulation of the AChR can be achieved in two ways (1) by binding of the directly acting cholinergic agonists to the AChR, triggering nicotinic or muscarinic... 

Nicotinic receptor A primary class of cholinergic receptors, named according to their affinity for nicotine, as well as certain other cholinergic agonists and antagonists. 

To understand the action of nicotine it is essential to understand the neurotransmitter acetylcholine (ACH), which we reviewed in Chapter 3. Nicotine stimulates the same receptors that are sensitive to ACH and therefore is a cholinergic agonist drug... 

Nicotine is a cholinergic agonist that has biphasic (stimulant and depressant) action. 

Therefore, the inclusion of an electron donating group such as the amino group has greatly increased the chemical and enzymatic stability of our cholinergic agonist. Unfortunately, it is found that carbachol shows very little selectivity between the muscarinic and nicotinic sites. 

Cartap is also an important insecticide acting at the nicotinic acetylcholine receptor site. It causes insects to stop feeding, is systemic, and has a low mammalian toxicity. It should therefore be a perfect insecticide. Cartap is not toxic per se, but is biologically converted to the cholinergic agonist nereistoxin, described later. 

The pharmacology of ACh in A. suum has been explored extensively (117,123). The muscle ACh receptor most resembles a vertebrate nicotinic receptor, and has properties of both neuromuscular and ganglionic receptors. Nicotinic receptors have also been reported in C. elegans, H. contortus and D. vitae (124 127). The anthelminthics morantel, pyrantel and levamisole are cholinergic agonists in A. suum (128) and C. elegans (124,129). 

Perspectives of the cholinergic approach Anticholinesterases M/muscarinic agonists Nicotinic agents Glutamatergic approach Medicinal chemistry... 

It is well known that the CNS has both muscarinic and nicotinic receptor sites (for a review, see De Robertis, 1975) thus the PI effect stimulated by ACh could be mediated by one or the other type of receptors. Scattered observations favor the view that the muscarinic receptors are related to the metabolism of PI. In particulate fractions Hokin Hokin (1958) found that the PI effect was blocked by atropine, and Schacht Agranoff (1973), In a synaptosomal fraction, observed that the ACh stimulation was insensitive to d-tubocurarine. To investigate this problem further, in addition to using appropriate cholinergic agonists and antagonists, an approach would be to take Into consideration the regional distribution of both types of receptors in the CNS. For example,... 

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). 

Nicotinic Receptor Agonists. There has been significant activity in the development of muscarinic cholinergic receptor agonists for dementia. In addition, agents that interact with nicotinic cholinergic receptors may also have therapeutic value. Nicotinic receptors have been reported to be... 

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