Adrenergic Neuron Blockers

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Adrenergic neuron blockers cause degradation of biogenic amines in neuron endings. These drugs can interfere with the synthesis, storage and release of norepinephrine, dopamine, and serotonin.

Reserpine: Reserpine is methyl ester 2a,11-dimethoxy-3-(3,4,5-trimethoxybenzoyloxy)-yohimban-1-carboxylic acid (12.3.1). Reserpine is one of the alkaloids isolated from a perennial shrub of the Rauwolfia family [67-72]. It can also be synthesized [73-76].

Reserpine causes a breakdown of norepinephrine, dopamine, and serotonin in neuron endings. It weakens intracellular uptake of biogenic amines and reduces the ability if storing them in vesicles. It is possible that reserpine acts on membrane vesicles, irreversibly inhibiting ATP-Mg2+ (adenosinetriphosphate) requiring process that is responsible for the uptake of biogenic amines in interneuronal vesicles. Breakdown of catecholamines is expressed by a decreased number of intraneuronal serotonin and dopamine.

Reserpine is used for treating hypertension; however, it is not the drug of choice because of a number of side effects. A number of drugs combined with other hypertensive agents— diuretics in particular—are based on reserpine. Reserpine is prescribed under a number of names, including serpasil, brinerdin, diupres, and others.

Guanethidine: Guanethidine, /¡-(l-azacyclooctyl)ethylguanidine (12.3.4), is synthesized in the following straightforward manner. Azocine is alkylated by chloracetonitrile, which forms 1-azocinylacetonitrile (12.3.2), which is reduced by lithium aluminum hydride into 1-(2-aminoethyl)azocine (12.3.3). Reacting this with S-methylthiourea gives guanethidine (12.3.4) [77-79].

Guanethidine Synthesis

Unlike adrenoblockers, guanethidine does not act on effector cells. It acts on branched ends of sympathetic peripheral nerve fibers and permeates into the neuron by the same mechanism of reverse uptake that returns norepinephrine from the synaptic cleft to neuron endings. Inside the neuron, guanethidine accumulates and competes with norepinephrine for storage space as granules. With an increase in guanethidine concentration, norepinephrine is replaced and thus the quantity of neurotransmitters capable of being released is reduced. In response to stimulation, the nerve may release guanethidine, which, however, is not an adrenergic receptor stimulant. In addition to this disturbance and the presence of stores of catecholamines in adrenergic nerve endings, guanethidine also acts on the stores of catecholamines in organs such as the heart, spleen, and aorta.

Since it does not pass through the blood-brain barrier, it does not act on the central sympathetic neurons.

Guanethidine is used for severe hypertension, where use of more universally accepted drugs is not successful. It is a very powerful and long-lasting drug, and its effects last for 2-3 days after using it. Synonyms of this drug are octadin, ismelin, sanotensin, and others.

Guanadrel: Guanadrel, (1,4-dioxaspiro[4,5]dec-2-ylmethyl)guanidine (12.3.8), is synthesized when cyclohexanone undergoes ketalization by 3-chloro-1,2-proandiol, forming 2-chloromethyl-1,4-dioxyspiro[4,5]decane (12.3.5), which is further akylated by sodium phthalimide. After alkyline hydrazinolysis, the resulting phthalimide derivative (12.3.6) is transformed into 2-aminomethyl-1,4-dioxyspiro[4,5]decane (12.3.7), which is reacted with S-methylthiourea, giving the desired guanadrel (12.3.8) [80-82].

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