Content
Whilst the aromatic amino acid L-tyrosine is
a common and extremely important precursor of alkaloids, L-phenylalanine is
less frequently utilized, and usually it contributes
only carbon atoms, e.g. C6C3, C6C2, or C6C1
units, without providing a nitrogen atom from its
amino group. Ephedrine (Figure 117), the main
alkaloid in species of Ephedra* (Ephedraceae) and
a valuable nasal decongestant and bronchial dilator,
is a prime example. Whilst ephedrine contains
the same carbon and nitrogen skeleton as
seen in phenylalanine, and L-phenylalanine is a precursor, only seven carbons, a C6C1 fragment,
are actually incorporated. It is found that phenylalanine
is metabolized, probably through cinnamic
acid to benzoic acid, and
this, perhaps as its coenzyme A ester, is acylated
with pyruvate, decarboxylation occurring during
the addition (Figure 117).
The use of pyruvate
as a nucleophilic reagent in this way is
unusual in secondary metabolism, but occurs in
primary metabolism during isoleucine and valine
biosynthesis. |
|
 |
| Figure 117 |
A thiamine PP-mediated mechanism
is suggested (Figure 118; compare decarboxylation
of pyruvate, page 21, and formation of
deoxyxylulose phosphate, page 170). This process
yields the diketone, and a transamination reaction
would then give cathinone (Figure 115).
 |
| Figure 118 |
Reduction of the carbonyl group from either
face provides the diastereomeric norephedrineor norpseudoephedrine (cathine). Finally, Nmethylation
would provide ephedrine or pseudoephedrine(Figure 117). Typically, all four of
the latter compounds can be found in Ephedraspecies, the proportions varying according to
species. Norpseudoephedrine is also a major constituent
of the leaves of khat* (Catha edulis; Celastraceae),
chewed in African and Arab countries as a
stimulant. Most of the CNS stimulant action comes from the more active cathinone, the corresponding
carbonyl derivative. These natural compounds
are structurally similar to the synthetic amfetamine/
dexamfetamine; (amphetamine/dexamphetamine)
(Figure 119) and have similar properties.
 |
| Figure 119 |
Ephedra
Ephedra or Ma Huang is one of the oldest known drugs, having being used by the
Chinese for at least 5000 years. It consists of the entire plant or tops of various Ephedra
species (Ephedraceae), including E. sinica and E. equisetina from China, and E. geriardiana,
E. intermedia and E. major from India and Pakistan. The plants are small bushes with slender
aerial stems and minute leaves, giving the appearance of being effectively leafless. The
plants typically contain 0.5-2.0% of alkaloids, according to species, and from 30-90% of the total alkaloids is (-)-ephedrine (Figure 117). Related structures, including the
diastereoisomeric (+)-pseudoephedrine and the demethyl analogues (-)-norephedrine and
(+)-norpseudoephedrine (Figure 117) are also present. In E. intermedia, the proportion of
pseudoephedrine exceeds that of ephedrine.
Ephedrine is an indirectly acting sympathomimetic amine with effects similar to noradrenaline. Lacking the phenolic groups of the catecholamines, it has onlyweak
action on adrenoreceptors, but it is able to displace noradrenaline from storage vesicles in the
nerve terminals, which can then act on receptors. It is orally active and has a longer duration
of action than noradrenaline. It also has bronchodilator activity, giving relief in asthma, plus
a vasoconstrictor action on mucous membranes, making it an effective nasal decongestant.
Pseudoephedrine is also widely used in compound cough and cold preparations and as a
decongestant. The ephedrine and pseudoephedrine used medicinally are usually synthetic.
One commercial synthesis of ephedrine involves a fermentation reaction on benzaldehyde
using brewer's yeast (Saccharomyces sp.), giving initially an alcohol, then reductive
condensation with methylamine yields (-)-ephedrine with very high enantioselectivity
(Figure 120). The fermentation reaction is similar to that shown in Figure 118, in that
an activated acetaldehyde bound to TPP is produced by the yeast by decarboxylation of
pyruvate, and this unit is added stereospecifically to benzaldehyde in an aldol-like reaction.
The herbal drug ephedra/Ma Huang is currently being traded as 'herbal ecstasy'.
Consumption gives CNS stimulation, but in high amounts can lead to hallucinations, paranoia,
and psychosis.
 |
| Figure 120 |
Khat
Khat, or Abyssinian tea, consists of the fresh leaves of Catha edulis (Celastraceae), a
small tree cultivated in Ethiopia, East and South Africa, and the Yemen. The leaves are
widely employed in African and Arabian countries, where they are chewed for a stimulant
effect. This traditional use alleviates hunger and fatigue, but also gives a sensation of
general well-being (compare coca, page 302). Users become cheerful and talkative, and
khat has become a social drug. Prolonged usage can lead to hypertension, insomnia, or
even mania. Khat consumption may lead to psychological dependence, but not normally
physical dependence. There is presently little usage outside of Africa and Arabia, although
this is increasing due to immigration from these areas. However, for maximum effects,
the leaves must be fresh, and this somewhat restricts international trade. Dried leaves
contain up to 1% cathine ((+)-norpseudoephedrine (Figure 119)), but young fresh leaves
contain (-)-cathinone (Figure 119) as the principal CNS stimulant. Cathinone has similar
pharmacological properties as the synthetic CNS stimulant (+)-amfetamine/dexamfetamine
(amphetamine/dexamphetamine) (Figure 119), with a similar potency. Both compounds act
by inducing release of catecholamines.
Medicinal use of amfetamine has declined markedly as drug dependence and the severe
depression generated on withdrawal have been appreciated. Nevertheless, amfetamine
abuse is significant. Amfetamines are taken orally, sniffed, or injected to give a long period
of CNS stimulation (hours to days). Users often then take a depressant drug (alcohol,
barbiturates, opioids) to terminate the effects. Users rapidly become dependent and develop
tolerance. The consumption of khat is not yet restricted in the UK, even though both
cathine and cathinone are now controlled drugs. It remains to be seen whether khat will be
reclassified and its use restricted in any way. Other amfetamine-like derivatives of note are
methoxymethylenedioxyamfetamine (MMDA) and methylenedioxymethamfetamine (MDMA)
(Figure 119). MMDA is thought to be formed in the body after ingestion of nutmeg (Myristica
fragrans; Myristicaceae), by an amination process on myristicin, and it may
be the agent responsible for the euphoric and hallucinogenic effects of nutmeg. MDMA is the
illicit drug Ecstasy, a synthetic amfetamine-like stimulant popular among young people. The
use of Ecstasy has resulted in a number of deaths, brought about by subsequent heatstroke
and dehydration.
 |
| Figure 121 |
The amide capsaicin (Figure 121) constitutes
the powerfully pungent principle in chilli peppers
(Capsicum annuum; Solanaceae). Apart from its
culinary importance, it is also used medicinally
in creams to counter neuralgia caused by herpes
infections and in other topical pain-relieving
preparations. The initial burning effect of capsaicin
is found to affect the pain receptors, making
them less sensitive. The aromatic portion of
capsaicin is derived from phenylalanine through
ferulic acid and vanillin (Figure 121, compare
page 141), this aldehyde being the substrate for transamination to give vanillylamine. The acid portion
of the amide structure is of polyketide origin,
with a branched-chain fatty acyl-CoA being produced
by chain extension of isobutyryl-CoA. This
starter unit is valine derived.
|
