Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5928_Библиотеки_им_академика_М_И_Перельмана
.pdf
38 2 Noradrenaline (norepinephrine)
https://t.me/med1917
Fig. 2.1: Adrenergic synapses.
2.4 Drugs that focus on noradrenaline biosynthesis: false
transmitters
The biosynthesis of catecholamines starts from L-tyrosine (Scheme 2.1).
Scheme 2.1: Biosynthesis of catecholamines.
Compounds capable of inhibiting each of these steps are known, although very few
may have clinical utility. The most successful molecular modification is the introduction of a methyl group at the α-position of the amino acid (Fig. 2.2).
2.5 Drugs that affect the release of stored noradrenaline 39
https://t.me/med1917
Fig. 2.2: α-(S)-Methyltyrosine and α-(S)-methyldopa.
α-Methyltyrosine inhibits tyrosine hydroxylase in the first step, which is the rate determining step of the sequence and, therefore, the ideal step for inhibition. Although
not useful in clinical practice, it is used as an experimental drug. α-Methyldopa is a
competitive inhibitor of
though its decarboxylation is slower than in the
L-dopa decarboxylase. It is a substrate of this enzyme, al-
L-dopa. Upon transformation into α-
methyldopamine and subsequently into α-methylnoradrenaline, a false transmitter is
produced. False transmitters are defined as substances that are not normally synthesized at the nerve endings. Instead, they are able to accumulate by the same transport
processes, to be released under the effect of the nerve impulse, and to act on the postsynaptic receptors, although with less potency than t he natural compound. Consequently, the storage of a false transmitter will lead to a reduction of the pulse passing
through the synapse. Methyldopa may be used as an antihypertensive drug.
Dopamine-β-hydroxylase can be inhibited by disulfiram, which is a nonspecific
blocker of oxidative enzymes (Fig. 2.3). It causes an unpleasant reaction when alcohol
intake occurs. It is used as a vulcanizer, seed disinfectant, fungicide, and, specifically,
in the treatment of alcoholism.
Fig. 2.3: Disulfiram.
2.5 Drugs that affect the release of stored noradrenaline
Since stimulation of the adrenergic system requires two consecutive processes of NA
release (from their sites of accumulation and then from the neuron to the synapse),
drugs that facilitate or block these processes offer an interesting opportunity for therapeutic control.
The alkaloid r eserpine is a drug capable of emptying the NA stored inside the
neuron (the biochemical mechanism is not known) so that the neurotransmitter is exposed to oxidation by MAO and ends up depleting it after a certain time (Scheme 2.2).
MAO, known since 1928, is an oxidizing enzyme that converts α-unsubstituted primary amines into aldehydes.
40 2 Noradrenaline (norepinephrine)
https://t.me/med1917
Scheme 2.2: Oxidative deamination caused by MAO.
Adrenergic transmission is interrupted because of the lack of neurotransmitter at presynaptic terminations. This is the basis of the antihypertensive action of reserpine,
which is accompanied by an important sedative effect (CNS depression). A certain separation of the hypotensive and sedative actions has been achieved by molecular modification. Thus, mediodespidine is a synthetic drug, equipotent to reserpine as a
hypotensive, but less potent as a sedative (Fig. 2.4).
Fig. 2.4: Reserpine and mediodespidine.
2.5 Drugs that affect the release of stored noradrenaline 41
https://t.me/med1917
In addition to reserpine, the antihypertensive drug rescinamine is also found in the roots
of different Asian, American, or African species of the genus Rauwolfia. In rescinamine,
the acyl group that esterifies to hydroxyl in C
is the 3,4,5-trimethoxycinnamoyl group.
18
Another drug that seems to empty the NA stored inside the neuron is guanethidine
(1960) (Scheme 2.4). Its main advantage over reserpine is that it does not produce CNS
depression, since it does not cross the BBB because of its strong positive ionic charge.
The protonation of the guanidino group gives rise to a cation that has a large resonance
stabilization (Scheme 2.3). Guanidines are among the strongest organic bases. Guanethidine is an antihypertensive agent that acts by interfering with the adrenergic transmission. It can be prepared from cycloheptanone via a Beckmann rearrangement.
Scheme 2.3: High basicity of guanidine.
Beckmann rearrangement is a reaction in which an oxime is converted into an amide
through treatment with a str ong concentrated acid, typically H
. This reaction is
2SO4
used industrially in the transformation of cyclohexanone oxime into ε-caprolactam,
from which nylon 6 is obtained. Preparation of guanethidine starts with a Beckmann
rearrangement from the oxime of cycloheptanone (Scheme 2.4). The mechanism involves, first of all, the conversion of the hydroxyl group into a good leaving group by
the action of sulfuric acid, which converts it to H
O+. Next, the methylene group that
3
Scheme 2.4: Conversion of cycloheptanone into the eight-membered lactam by a Beckmann rearrangement.
42 2 Noradrenaline (norepinephrine)
https://t.me/med1917
is anti to the leaving group migrates toward nitrogen, expelling the le aving group.
The intermediate carbocation generated is trapped by water to give an intermediate
that loses a proton and finally undergoes tautomerism to the eight-membered lactam.
The total synthesis of guanethidine is shown in Scheme 2.5. A reaction of Smethylisothiouronium chloride with primary amines is the general procedure for the
preparation of monosubstituted guanidines.
Scheme 2.5: Synthesis of guanethidine.
Guanethidine first causes a hypertensive reaction, followed by a long-term hypotension. It is used in cases of severe and malignant hypertension.
2.6 Mechanism of action of MAO
Many enzymes require cofactors, which are metal ions, such as Zn2+,Mg2+,Mn2+,Fe2+,
2+
, or organic molecules called coenzymes (in general, essential vitamins or their
Cu
metabolites).
2.7 Adrenergic indirect drugs 43
https://t.me/med1917
Vitamin B2, or riboflavin, is a benzopteridine derivative with a reduced ribos e
chain at position 10. As a component of flavin-adenine dinucleotide (FAD), it is an electron and proton carrier due to the stability of the radical anion that occurs when an
electron is added (Fig. 2.5).
Fig. 2.5: Riboflavin (vitamin B2).
MAOs are flavoproteins that catalyze the ox idation of primary amines to aldehydes.
The FAD (Fl
diate (Scheme 2.6), which adds a proton to yield the radical FlH
another electron yields the FlH
to the reduced form FlH
) cofactor acts as an electron acceptor to give an anion radical interme-
ox
–
anion, and the final addition of another proton leads
(FADH2). This process is coupled with oxidation of the sub-
2
•
. Further addition of
strate. It involves the abstraction of an electron to yield a radical cation, the subsequent loss of a proton to yield a radical, and the loss of another electron to yield an
iminium cation. The iminium cation is then spontaneously hydrolyzed to yield ammonia and the corresponding aldehyde. Reoxidation of the cofactor by molecular oxygen
completes the catalytic cycle.
2.7 Adrenergic indirect drugs
Indirect stimulants, or adrenergic agonists, are compounds that do not bind to adrenergic receptors, but stimulate the sympathetic transmission through causing an increase in the NA concentration that reaches these receptors.
However, the mode of action is rarely strictly direct or indirect. Given the structural similarity between the agonists of b oth types, these drugs frequently have a
mixed action. In addition, many of the compounds with indirect adrenergic action (especially those less polar) are also CNS stimulants. They are used clinically in several
cases, such as anorexics or appetite depressants and as false transmitters. Either of
these actions may predominate in each concrete compound.
From a structural point of view, most of the indirect adrenergic agents are phenethylamines that come either from a molecular modification of the NA neurotransmitter or from the ephedrine alkaloid, with a mixed adrenergic action (Fig. 2.6).
Natural ephedrine is the
D-(–)-pseudoephedrine. Synthetic compounds with an indirect or mixed action can be
derived from them, such as those shown in Fig. 2.7.
D-(–)-erythro isomer, which is 36 times more potent than
44 2 Noradrenaline (norepinephrine)
https://t.me/med1917
Scheme 2.6: The MAO redox mechanism.
2.7 Adrenergic indirect drugs 45
https://t.me/med1917
Fig. 2.6: Natural phenethylamines.
Fig. 2.7: Synthetic compounds with indirect or mixed actions.
46 2 Noradrenaline (norepinephrine)
https://t.me/med1917
Amphetamine differs from ephedrine in that it lacks both N-Me and hydroxyl groups.
The lack of the latter group decreases its polarity, so that it is more easily transportable toward the CNS. The compound is thus used primarily as a CNS stimulant. Note
the major structural differences between the indirect adrenergic drugs and NA:
1. Indirect adrenergic drugs do not have the phenolic OH group at positions 3 and 4
(hydroxyamphetamine has a mixed action). This increases their oral absorption
and penetration into the CNS, so that most adrenergic drugs (amphetamines and
phentermine) act as central stimulants.
2. In general, indirect adrenergic drugs lack the benzyl OH group, although it is still
present in some drugs (ephedrine and propadrine). Those that have it, being
more polar compounds, are always lesser CNS stimulants.
3. Indirect adrenergic drugs usually have one methyl group (and sometimes two) on
the nitrogen atom alpha. This methyl group, similar to that found in methyldopa
that yields the false α-methylnoradrenaline transmitter, significantly reduces the
direct action. At the same time, it increases the oral efficacy, because it prevents
the degradation of the drug by MAO and increases the lipophilicity of the amine.
A methyl group in beta eliminates the activity.
4. The phenyl group may be replaced by other aromatic and even cycloalkane rings;
for example, as is the case for the indirect adrenergic drugs cyclopentamine and
propylhexedrine (Fig. 2.8).
Fig. 2.8: Cyclopentamine and propylhexedrine.
2.8 Catechol-O-methyltransferase inhibitors (COMT)
COMT catalyzes the methylation of the phenolic hydroxyl group in catechol (1,2benzenediol) structures. The mechanism is shown in Scheme 2.7.
2.9 Direct adrenergic drugs (postsynaptic agonists)
The first postsynaptic phenomenon that occurs during the adrenergic nerve transmission is the binding of norepinephrine to its receptors. Chemical groups necessary for
the compound to mimic the action of NA have been determined through SARs. In a
schematic form, these structural requirements are as follows (Fig. 2.9).
2.9 Direct adrenergic drugs (postsynaptic agonists) 47
https://t.me/med1917
Scheme 2.7: O-Methylation of NA, catalyzed by COMT.
Fig. 2.9: SARs necessary for a compound to mimic the NA action.
The most interesting modification was the substitution at the nitrogen atom. Catecholamines have a dual action on the tissues: a contractile effect, called α, and a relaxation
effect, called β. The existence of two types of adrenergic receptors, also called α and β,
responsible in the first approximation for those excitatory and inhibitory actions, was
established. This division was established on the basis of their responses to a series of
agonists with a different substitution at the nitrogen atom (Fig. 2.10):
– Receptor α has a decreasing adrenaline > NA > isoprenaline sensitivity
– Receptor β has a decreasing isoprenaline > adrenaline > NA sensitivity
Adrenergic receptors predominantly play a role in the smooth muscle excitation.
β-Adrenergics are associated with inhibition of the smooth muscle tone (vasodilatation
and bronchodilation), even with that of the bowel and the myocardium stimulus.
Соседние файлы в папке Библиотека им академика М.И. Перельмана