How To Number The Structure Of Reserpine

Figure 16.7 • Mechanism of ^-receptor-mediated signal transduction.

been proposed that the adrenergic agonist-binding site is within the TM-spanning regions, whereas the cytoplasmic regions of the receptor interact with the Gs protein. Specifically, aspartic acid residue 113 in transmembrane region III (TM-III) acts as the counterion to the cationic amino group of the adrenergic agonist. This aspartic acid residue is found not only in a comparable position in all the other adrenoceptors but also in other known GPCRs that bind substrates having positively charged nitrogens in their structure. Two serine residues, at positions 204 and 207 in TM-V, form H-bonds with the catechol OH groups of the adrenergic agonists. The jS-OH group of adrenergic agonists is thought to form an H-bond with the side chain of asparagine 293 in TM-VI, whereas the phenylalanine residue at position 290 in the same TM-VI is believed to interact with the catechol ring (Fig. 16.8). Because the serine is in the fifth membrane-spanning region and the aspartic acid is in the third, it is likely that CAs bind parallel to the plane of the membrane, forming a bridge between the two TM-spanning regions.

Molecular biological techniques have shown the existence of adrenergic receptor polymorphism for both the a-and j-receptors. It is postulated that such polymorphisms may be an important factor behind individual differences in responses to drugs acting at these receptors. In addition, there may be an association between the polymorphisms of adrenergic receptor genes and disease states.29


Drugs Affecting Catecholamine Biosynthesis

Metyrosine (a-Methyl-L-tyrosine, Demser) Although inhibition of any of the three enzymes involved in CA biosynthesis should decrease CAs, inhibitors of the first and the rate-limiting enzyme TH would be the most effective. As such, metyrosine is a much more effective competitive inhibitor of E and NE production than agents that inhibit any of the other enzymes involved in CA biosynthesis. It is often possible to "fool" the enzymes into accepting a structurally similar and unnatural substrate such as mety-rosine. Metyrosine differs structurally from tyrosine only in the presence of an a-methyl group (Fig. 16.9). It is one example of a CA-biosynthesis inhibitor in clinical use.30 Although metyrosine is used as a racemic mixture, it is the ( —) isomer that possesses the inhibitory activity. Metyrosine, which is given orally in dosages ranging from

Reserpine Vmat Binding Model
Figure 16.8 • Model of ß2-AR binding sites: Illustration of the Easson-Stedman hypothesis representing the interaction of three critical pharmacophore groups of norepinephrine with the complementary binding areas on the adrenergic receptor as suggested by site-directed mutagenesis studies.
Easson Stedman Hypothesis

L-Tyrosine (a precursor of NE and a substrate of TH) Epinephrine (E): T bp

Figure 16.9 • Mechanism of action of metyrosine.

L-Tyrosine (a precursor of NE and a substrate of TH) Epinephrine (E): T bp

Figure 16.9 • Mechanism of action of metyrosine.

Easson Stedman Hypothesis

a-Methyl-m-tyrosine a-Methyl-m-tyramine Metaraminol (aragonist)

Figure 16.10 • Metabolic activation of a-methyl-m-tyrosine to metaraminol.

1 to 4 g/day, is used principally for the preoperative management of pheochromocytoma, chromaffin cell tumors that produce large amounts of NE and E. Although these adrenal medullary tumors are often benign, patients frequently suffer hypertensive episodes. Metyrosine reduces the frequency and severity of these episodes by significantly lowering CA production (35%-80%). The drug is polar (log P = 0.73) and excreted mainly unchanged in the urine. Because of its limited solubility in water caused by intramolecular bonding of the zwitterions, crystalluria is a potential serious side effect. It can be minimized by maintaining a daily urine volume of more than 2 L. Inhibitors of CA synthesis have limited clinical utility because such agents nonspecifically inhibit the formation of all CAs and result in many side effects. Sedation is the most common side effect of this drug.

A similar example is the use of a-methyl-m-tyrosine in the treatment of shock. It differs structurally from metyrosine only in the presence of m-OH instead of p-OH in metyrosine. This unnatural amino acid is accepted by the enzymes of the biosynthetic pathway and converted to metaraminol (an a-agonist) as shown (Fig. 16.10).

Inhibitors of AADC (e.g., carbidopa) have proven to be clinically useful, but not as modulators of peripheral adren-ergic transmission. Rather these agents are used to inhibit the metabolism of drug l-DOPA administered in the treatment of Parkinson disease (Chapter 13).

Drugs Affecting Catecholamine Storage and Release

Reserpine (an NT Depleter). Reserpine, a prototypical and historically important drug, is an indole alkaloid obtained from the root of Rauwolfia serpentina found in India.

As is typical of many indole alkaloids, reserpine is susceptible to decomposition by light and oxidation. Reserpine is extensively metabolized through hydrolysis of the ester function at position 18 and yields methyl reserpate and 3,4,5-trimethoxybenzoic acid. It not only depletes the vesicle storage of NE in sympathetic neurons in PNS, neurons of the CNS, and E in the adrenal medulla, but also depletes the storage of serotonin and DA in their respective neurons in the brain. Reserpine binds extremely tightly with and blocks VMAT that transports NE and other biogenic amines from the cytoplasm into the storage vesicles.31 Thus in sympathetic neurons, NE, which normally is transported into the storage vesicles, is instead metabolized by mitochondrial MAO in the cytoplasm. In addition, there is a gradual loss of vesicle-stored NE as it is used up by release resulting from sympathetic nerve activity so that the storage vesicles eventually become dysfunctional. The end result is a depletion of NE in the sympathetic neuron. Analogous effects are seen in the adrenal medulla with E and with 5-HT in serotonergic neurons.

When reserpine is given orally, its maximum effect is seen after a couple of weeks. A sustained effect up to several weeks is seen after the last dose has been given. This is because the tight binding of reserpine to storage vesicles continues for a prolonged time, and recovery of sympathetic function requires synthesis of new vesicles over a period of days to weeks after discontinuation of the drug. Most adverse effects of reserpine (log P = 4.37) are caused by CNS effects because it readily enters the CNS. Sedation and inability to concentrate or perform complex tasks are the most common adverse effects. More serious is the occasional psychotic depression that can lead to suicide, which support monoamine theory of pathology of depression. Agents with fewer side effects have largely replaced reserpine in clinical use.

Reserpine Metabolism

Chapter 16 # Adrenergic Agents 531 guanidino moiety

Guanethidine (Ismelin) and guanadrel (Hylorel) are seldom used orally active antihypertensives. Drugs of this type enter the adrenergic neuron by way of the uptake-1 process and accumulate within the neuronal storage vesicles. There they bind to the storage vesicles and stabilize the neuronal storage vesicle membranes, making them less responsive to nerve impulses. The ability of the vesicles to fuse with the neuronal membrane is also diminished, resulting in inhibition of NE release into the synaptic cleft in response to a neuronal impulse and generalized decrease in sympathetic tone. Long-term administration of some of these agents also can produce a depletion of NE stores in sympathetic neurons.

Both neuronal blocking drugs possess a guanidino moiety [CNHC(=NH)NH2], which is attached to either a hexahy-droazocinyl ring linked by an ethyl group as in guanethidine, or a dioxaspirodecyl ring linked by a methyl group as in guanadrel. The presence of the more basic guanidino group (pKa >12) than the ordinary amino group in these drugs means that at physiological pH, they are essentially completely protonated. Thus, these agents do not get into the CNS. As a result, this drug has none of the central effects seen with many of the other antihypertensive agents described in this chapter. Guanethidine contains two basic nitrogen atoms with pKa values of 9.0 and 13.43, and can therefore form guanethidine monosulfate (C10H22N4 • H2SO4) or guanethidine sulfate [(C10H22N4)2 • H2SO4].

Although guanethidine and guanadrel have virtually the same mechanism of action on sympathetic neurons, they differ in their pharmacokinetic properties. For example, although guanethidine is absorbed incompletely after oral administration (3%-50%), guanadrel is well absorbed, with a bioavailability of 85%.32 These two agents also differ in terms of half-life: Guanethidine has a half-life of about 5 days, whereas guanadrel has a half-life of 12 hours. Both agents are partially metabolized (—50%) by the liver, and both are used to treat moderate-to-severe hypertension, either alone or in combination with another antihypertensive agent.

Was this article helpful?

0 0
Conquering Fear In The 21th Century

Conquering Fear In The 21th Century

The Ultimate Guide To Overcoming Fear And Getting Breakthroughs. Fear is without doubt among the strongest and most influential emotional responses we have, and it may act as both a protective and destructive force depending upon the situation.

Get My Free Ebook


  • selamawit
    Which isomer of metyrosin possesses the inhibitory activity?
    6 years ago
  • Anna
    How to number the structure of reserpine?
    4 years ago

Post a comment