O Cholinergic Blocking Agents

A wide variety of tissues respond to ACh released by the neuron or exogenously administered chemicals to mimic this neurotransmitter's action. Peripheral cholinergic receptors are located at parasympathetic postganglionic nerve endings in smooth muscle, sympathetic and parasympathetic ganglia, and neuromuscular junctions in skeletal muscle. Although ACh activates these receptors, there are antagonists that are selective for each. Atropine is an effective blocking agent at parasympathetic postganglionic terminals. Like most classic blocking agents, it acts on all muscarinic receptor subtypes. d-Tubocurarine blocks the effect of ACh on skeletal muscle, which is activated by N1 nicotinic receptors. Hexamethonium blocks transition at N2 nicotinic receptors located in auto-nomic ganglia.

Anticholinergic action by drugs and chemicals apparently depends on their ability to reduce the number of free receptors that can interact with ACh. The theories of Stephenson67 and Ariens68 have explained the relationship between drug-receptor interactions and the observed biological response (see Chapter 2). These theories indicate that the amount of drug-receptor complex formed at a given time depends on the affinity of the drug for the receptor and that a drug that acts as an agonist must also possess another property, called efficacy or intrinsic activity. Another explanation of drug-receptor interactions, the Paton rate theory,69 defines a biological stimulus as proportional to the rate of drug-receptor interactions (see Chapter 2). Both of these theories are compatible with the concept that a blocking agent that has high affinity for the receptor may decrease the number of available free receptors and the efficiency of the endogenous neurotransmitter.

Structure-Activity Relationships

A wide variety of compounds possess anticholinergic activity. The development of such compounds has been largely empiric and based principally on atropine as the prototype. Nevertheless, structural permutations have resulted in compounds that do not have obvious relationships to the parent molecule. The following classification delineates the major chemical types encountered:

• Solanaceous alkaloids and synthetic analogs

• Synthetic aminoalcohol esters

• Aminoalcohol ethers

• Aminoalcohols

• Aminoamides

• Miscellaneous

• Papaveraceous

The chemical classification of anticholinergics acting on parasympathetic postganglionic nerve endings is complicated somewhat because some agents, especially the quaternary ammonium derivatives, act on the ganglia that have a muscarinic component to their stimulation pattern and, at high doses, at the neuromuscular junction in skeletal muscle.

There are several ways in which the structure-activity relationship could be considered, but in this discussion we follow, in general, the considerations of Long et al.,70 who based their postulations on the 1-hyoscyamine molecule being one of the most active anticholinergics and, therefore, having an optimal arrangement of groups.

Anticholinergic compounds may be considered chemicals that have some similarity to ACh but contain additional substituents that enhance their binding to the cholinergic receptor.

Benzilylcarbocholine

As depicted above, an anticholinergic agent may contain a quaternary ammonium function or a tertiary amine that is protonated in the biophase to form a cationic species. The nitrogen is separated from a pivotal carbon atom by a chain that may include an ester, ether, or hydrocarbon moiety. The substituent groups A and B contain at least one aromatic moiety capable of van der Waals interactions to the receptor surface and one cycloaliphatic or other hydrocarbon moiety for hydrophobic bonding interactions. C may be hydroxyl or carboxamide to undergo hydrogen bonding with the receptor.

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