The active principle of opium is morphine and this compound is still one
of the most effective painkillers available to medicine. It is especially good for treating
dull, constant pain rather than sharp, periodic pain. It acts in the brain and appears to
work by elevating the pain threshold, thus decreasing the brain's awareness of pain.
Unfortunately, it has a large number of side-effects which include the following:
• depression of the respiratory centre
• constipation
• excitation
• euphoria
• nausea
• pupil constriction
• tolerance
• dependence
Some side-effects are not particularly serious. Some, in fact, can be advantageous.
Euphoria, for example, is a useful side-effect when treating pain in terminally ill
patients. Other side-effects, such as constipation, are uncomfortable but can give
clues as to other possible uses for opiate-like structures. For example, opiate structures
are widely used in cough medicines and the treatment of diarrhoea.
The dangerous side-effects of morphine are those of tolerance and dependence,
allied with the effects morphine can have on breathing. In fact, the most common
cause of death from a morphine overdose is by suffocation. Tolerance and dependence
in the one drug are particularly dangerous and lead to severe withdrawal symptoms
when the drug is no longer taken.
Withdrawal symptoms associated with morphine include anorexia, weight loss,
pupil dilation, chills, excessive sweating, abdominal cramps, muscle spasms, hyperirritability,
lacrimation, tremor, increased heart rate, and increased blood pressure.
No wonder addicts find it hard to kick the habit!
250 The opium analgesics
The isolation and structural identification of morphine mark the first two stages of
our story and have already been described. The molecule contains five rings labelled
A-E and has a pronounced T shape. It is basic because of the tertiary amino group,
but it also contains a phenolic group, an alcohol group, an aromatic ring, an ether
bridge, and a double bond. The next stage in the procedure is to find out which of
these functional groups is essential to the analgesic activity.
12.2.2 Structure-activity relationships
The story of how morphine's secrets were uncovered is presented here in a logical
step-by-step fashion. However, in reality this was not how the problem was tackled at
the time. Different compounds were made in a random fashion depending on the ease
of synthesis, and the logical pattern followed on from the results obtained. By
presenting the development of morphine in the following manner, we are distorting
history, but we do get a better idea of the general strategies and the logical approach to
drug development as a whole.
The first and easiest morphine analogues which can be made are those involving
peripheral modifications of the molecule (that is, changes which do not affect the basic
skeleton of the molecule). In this approach, we are looking at the different functional
groups and discovering whether they are needed or not.
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