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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5928_Библиотеки_им_академика_М_И_Перельмана
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108 5 Amino acid neurotransmitters
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Scheme 5.9: Flurazepam synthesis.
5.6.1.4.1 A ring
The presence of an electron-withdrawing substituent at position 7 is necessary. In the
examples cited was chlorine, but –NO
, –CF3, Br, –CN, etc. are also suitable. Replace-
2
ment at positions 6, 8, or 9 reduces potency. One example is nitrazepam, a drug used
primarily as a sedative-hypnotic (Fig. 5.6).
5.6.1.4.2 B ring
The presence of a CH
stituents are bulkier, the activity is reduced. However, groups that can be removed by
metabolization as –CH
The presence of an OH at position 3 (oxazepam) reduces potency, but favors the
anxiolytic action against undesirable side effects, such as fatigue and physical dependence. Furthermore, the drug is eliminated more rapidly. The esters and carbamates
of this 3-OH are useful prodrugs. At position 3, a carboxylate group (clorazepate dipotassium, Tranxilium
Fig. 5.6: Nitrazepam (1,3-dihydro-5-phenyl-7-nitro-1,4-benzodiazepine-2-
one, Mogadon
group in N-1 usually increases potency (e.g., diazepam). If sub-
3
–CH2–NEt2in flurazepam are acceptable.
2
®
) may also be introduced (Fig. 5.7).
®
).
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Fig. 5.7: Clorazepate, also known as clorazepate dipotassium (Tranxilium®, 1972).
5.6.1.4.3 C ring
At position 5 of the benzodiazepines, a phenyl or aryl substituent must be found for
optimum activity. The alkyl, cycloalkyl, or heterocyclic groups usually give rise to less
potent drugs, although there are exceptions such as bromazepam, a Bzd in which a 2pyridyl residue in 5 is found (Fig. 5.8).
Substitution in the 5-phenyl group for electron-withdrawing groups in ortho (F, Cl), or
disubstitution in ortho–ortho′, increases the activity (flurazepam). The presence of
groups at meta or para invariably reduces potency.
5.6.1.4.4 Other rings (fusion of new rings)
In recent years, research in the field of Bzds has been directed mainly at the fusion of
new rings to the basic system, as well as the substitution of ring A by nuclei of heterocyclic nature. Triazolam and ripazepam are examples of these modifications (Fig. 5.9).
5.6.2 Fixation of steroids to GABA
It has been observed that many steroids such as progesterone (Fig. 5.10) and some glucocorticoids produce actions in the CNS through their interaction with a binding site
located at the GABA
Fig. 5.8: Bromazepam (anxiolytic).
A
receptor, which is not the same as that of barbiturates, but pro-
A
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Fig. 5.9: Triazolam and ripazepam.
ducing very similar effects. Changes in progesterone levels can alter one’s mood and
sense of well-being. This is because allopregnanolone, the progesterone metabolite, is
a GABA-A receptor agonist. This means that allopregnanolone binds to GABA
recep-
A
tors. Thus, with higher progesterone levels, GABA function increases.
Fig. 5.10: Progesterone and allopregnanolone.
5.6.3 Other drugs related to benzodiazepines
Zopiclone and zolpidem (Fig. 5.11) are two drugs that act as agonists on the Bzd receptors.
They are anxiolytic although, unlike Bzds, present more pronounced hypnotic and sedative effects.
5.6.4 Barbituric acids (or barbiturates)
Although they are still in use, the addiction and toxicity problems associated with barbiturates suggest their gradual substitution with Bzds. In spite of the fact that the activity
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Fig. 5.11: Agonists of the Bzd receptor.
of barbituric acids was initially considered to be related only to their physicochemical
properties (especially lipophilicity), they are now known to act by stabilizing the open
form of the chloride channel in the vicinity of the allosteric receptor of GABA, analogously to Bzds.
Barbiturates are derivatives of 2,4,6-trihydroxypyrimidine, for which we can con-
sider the tautomeric equilibrium shown in Scheme 5.10.
Scheme 5.10: Tautomeric equilibrium in 5,5-disubstituted derivatives.
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Barbituric acid itself lacks hypnotic properties due to its high acidity (pKa= 4.1), which
causes it to be totally ionized at physiological pH, so it will not pass the BBB. Also fully
alkylated derivatives at positions 1, 3, 5, 5 are lacking in hypnotic effe cts. Therefore,
the sedative action requires the presence of lipophilic substituents at position 5 of the
ring (5,5-disubstituted derivatives), and moreover, the existence of at least one H that
allows tautomerism and ionization. In 5,5-disubstituted and 1,5,5-trisubstituted derivatives, the tautomer with the trilactim structure is not possible so the acidity is lower
= 7.6−8.5, Scheme 5.10), and at the same time, depending on the nature of the sub-
(pK
a
stituents they may present the ideal lipophilic characteristics suitable for their pharmacological activity (Fig. 5.12).
Fig. 5.12: Active derivatives of barbituric acid.
Sandberg enunciated a fundamental postulate: for a barbiturate to have good hypnotic-sedative activity, it must be a weak acid and have a lipid/water partition coefficient between certain limits (log P
≈ 2). This fact agrees with the need for a double
0
lipophilic-hydrophilic character. Consequently, for a barbiturate to be active it must
meet the following requirements:
1. It must be disubstituted at positions 5, 5′.
2. For each substituent, each of which must independently have at most 6 C → R, R′ ≤ 6C.
3. The sum of the substituents must not be greater than 10 → R+R′ ≤ 10 C.
Depending on the nature of the lipophilic groups, the effect of barbituric acids may vary
and even be accompanied by an anticonvulsive effect. The intensity effect can reach the
degree of general anesthesia, when the dose is sufficiently high. However, these types of
compounds should be treated with caution, as the dose increases the respiratory depression they cause. Table 5.1 shows the most frequent barbiturates, classified according to
the duration of the effect (see Chapter 8 of Volume 1 for some representative syntheses).
Substitution of the carbonyl group at position 2 by a thiocarbonyl group leads to
thiobarbituric acids, which are characterized by their ultra-short effect. They are usually
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Table 5.1: Classification of barbiturates according to their structures and effects.
RR′ R″ X
Prolonged effect Et Ph H O
Phenobarbital Et Et CH
Metarbital
Intermediate effect Et H O
Pentobarbital
Ultra short effect
Hexobarbital
CH
CH
O
O
Thiopental
Et H S
used as anesthetics intravenously for this reason. Long-acting barbiturates are used in
the treatment of epilepsy and the preservation of the sedative character during the day,
in states of anxiety and tension. Those of intermediate and short effects are used as hypnotics and sedatives in insomnia and for pre-anesthesia. Barbiturates have an effect on
basal anesthesia. See Chapter 8 of Volume 1 for some characteristic syntheses.
According to the sum of the substituents at position 5, the classification of barbi-
turates is made (Fig. 5.13).
Fig. 5.13: Classification of barbiturates according to substituents at positions 5, 5ʹ.
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The type of effect conditions certain indications:
– PROLONGED EFFECT
– INTERMEDIATE EFFECT
– SHORT AND ULTRA-SHORT EFFECT
SEDATIVE and ANTICONVULSIVANT DRUGS
HYPNOTICS and SEDATIVES
GENERAL ANESTHETICS
Their action is attributed to the level of thalamus and ascending reticular formation
that interferes with the transmission of the nerve impulses toward the cortex.
5.7 Fundamentals
Presynaptic modulators
Vigabatrin (antiepileptic) → GABA-AT suicide inhibitor
Sodium valproate (antiepileptic) → SSADH inhibitor
postsynaptic modulators
GABA
A
Bzds (Librium
Other agonists: Zolpidem
Barbituric acids (Sandberg rules): structures and therapeutic applications
Bzds and newer non-Bzd hypnotic drugs are now preferred over barbiturates for
most of clinical uses because they have a wider therapeutic index, their tolerance develops more slowly, and their liability for abuse is lower than that of barbiturates
®
, diazepam, etc.): SARs and syntheses
6 Peptides as neurotransmitters: narcotic analgesics
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6.1 Goals
– To introduce the reader to the need for pure analgesic drugs
– Morphine as a prototype of new analgesics
– To introduce the reader to the research in this field and to the future develop-
ment of μ-antagonists, κ-agonists that do not have activity against the σ-receptor
Clarification: Opioid receptors (the term OPIATE refers to the origin of the substance
with respect to opium, i.e., they are substances that are extracted from the capsule of
the opium plant. By extension, the chemical products derived from morphine are also
called this way. The term OPIOID is used to designate those endogenous or exogenous
substances that have an effect analogous to that of morphine and have intrinsic activity. Not all opioids are opiates, nor are all opiates opioids).
6.2 Morphine
The active principle of opium is morphine (Fig. 6.1) and this compound is still one of
the most effective analgesics available in medicine. Morphine is especially suited to
the treatment of constant, dull pain rather than periodic and sharp pain.
Fig. 6.1: Morphine.
It acts on the brain and seems to raise the threshold for pain, decreasing the awareness of pain in the brain. It has many side effects such as
– depression of the respiratory center
– excitement
– euphoria
– nausea
– tolerance
– dependence
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One of the salient side effects of morphine use is the physical or psychological dependence on drug symptoms and the ensuing withdrawal symptoms when drug consumption is interrupted. Tolerance occurs when a person needs to take a drug in ever
higher doses to achieve the same desired effect, such as euphoria or pain relief, than
before.
Morphine possesses five stereocenters of configurations 5R,6S,9R,13S, and 14R.
The molecule contains five rings (called A–E) and has a T-shape. It is basic because of
the tertiary amino group and also contains a phenolic group, an alcoholic group, an
aromatic ring, an ethereal bridge, and a double bond (Fig. 6.1).
6.2.1 Structure–activity relationships of morphine
6.2.1.1 The phenolic group
Codeine (Fig. 6.2) is used for the treatment of moderate pain and coughs. When methylating the phenolic group, analgesic activity drops drastically (0.1% of that of morphine, on isolated receptors).
Fig. 6.2: Decrease of the analgesic activity as the size of the R group increases at position 3.
However, the analgesic effect of codeine when administered to patients is 20% of that
of morphine: codeine can be metabolized in the liver to yield morphine (it is a
prodrug).
6.2.1.2 Alcohol at position 6
The results displayed in Fig. 6.3 show that neither masking nor the complete loss of
the alcohol group decrease analgesic activity and in fact exert the opposite effect.
It is interesting to compare the activities of morphine, 6-acetylmorphine, and heroin (Fig. 6.4). The most active compound of the three (and the most dangerous) is 6acetylmorphine, which is 4 times more active than morphine. Heroin is twice as active as morphine, but less active than 6-acetylmorphine. Let us try to explain these
facts.
6-Acetylmorphine is less polar than morphine and will enter the brain more easily than morphine. The phenolic group is free and will interact immediately with the
Fig. 6.3: Effect of the loss of the alcoholic group on analgesic activity.
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6.2 Morphine 117
Fig. 6.4: Heroin.
analgesic receptors. Heroin is the least polar and will be the most effective of t he
three to cross the BBB. However, before it can act, the acetyl group of the phenolic
group has to be eliminated by esterases in the brain. In short, the 6-hydroxyl group is
not required for analgesic activity and its elimination may be beneficial for such
activity.
6.2.1.3 The 7–8 double bond
Several analogs, including dihydromorphine (Fig. 6.5), demonstrate that the double
bond is not necessary for analgesic activity.
Fig. 6.5: Dihydromorphine.
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