Part
2
Basic
Opioid Pharmacology
All
natural and synthetic opioids exhibit a three dimensional T-shaped
configuration (Barchas, Berger, Ciaranello and Elliott, 1977). This T-shaped
molecule has two broad hydrophobic surfaces which are at right angles and a
methylated nitrogen which is usually charged at physiological pH. The charged
nitrogen is essential for activity and lies in one of the hydrophobic planes.
A hydroxyl group at carbon 3 on the other plane is also essential. This
configuration which all opioids have is called the piperidine
ring. Figure 1 is the structure of morphine with the
piperidine
ring indicated by bold lines. Simple changes on the morphine molecule produces
several semisynthetic derivatives. Diacetylmorphine, or heroin is made from
the morphine molecule by the acetylation of derivatives of the natural opium
alkaloids, there are a number of other structurally distinct chemical classes
of both the phenolic and the alcoholic OH groups (see Table 1). In addition to
morphine, codeine and the semisynthetic drugs with pharmacological actions
similar to those of morphine (Gilman, Rail, Niles and Taylor, 1990). These
groups although diverse share commonalties including the capacity to produce
analgesia, respiratory depression, gastrointestinal spasm, and morphine-like
physical dependence. These
compounds include the morphinians, benzomorphans, methadones,
phenylpiperidines and propionanilides. While two dimensional representatives
of the compounds appear to be quite different, three dimensional molecular
models show certain common characteristics.
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FFiFigure 1.
The Morphine Molecule. The
structure of morphine and all opium derivatives are characterized by the
piperdine ring which is indicated with bold lines. From Gilman, Rail, Niles,
Taylor, Goodman
and Gilmans ThThe
Pharmacological Basis of Therapeutics (1990).
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Table 1.
Structures of Opioid Agonists and Antagonists Chemically
Related to Morphine. Simple changes at positions
3, 6 and 17 of the morphine molecule (see Figure 1) can create dramatic
changes in the action of a compound. From Gilman, Rail, Niles, Taylor, Goodman and Gilmans The
Pharmacological Basis of Therapeutics (1990).
Endogenous
Opioids
The
term endorphin is used to characterize a group of endogenous peptides whose
pharmacological action mimics that of opium and its analogs (Gilman, Rail, Niles
and Taylor, 1990). The endogenous opioid system is complex with a multiplicity
of functions within any given organism (Goldstein, 1994). There exists about two
dozen known endogenous opioids which belong to one of three endogenous opioid
systems: 1) the endorphin system, 2) the enkephalins, and 3) the dynorphin
system.
The endogenous opioid system may play a role in a wide
variety functions such as, the production of analgesia, attention, memory,
catatonia, schizophrenia, manic depression, immune function, endocrine function,
appetite regulation, sexual behavior,
postpartum depression, release of several hormones, locomotor activity,
anticonvulsant activity, body temperature regulation, meiosis (pin point
pupils), shock from trauma, respiration, sleep, drug dependence, anxiety,
stress, mood and behavior (Gilman, Rail, Niles and Taylor, 1990; Goldstein,
1994).
Endorphins
are peptides. A peptide is a biologically active substance composed of amino
acids that are produced in neurons. Today peptides are considered to be a
distinct and separate group of psychoactive substances in the brain (Goldstein,
1994).
The
Target of Action: The Receptor
Most
psychoactive drugs exert their action at a receptor. This can be thought of as a
“lock and key” with the key as the drug opening the lock, or receptor.
Opiate receptors can be broken down further into types: the m (mu) receptor
prefers morphine, heroin and methadone, the e (epsilon) receptor prefers
b-endorphin (beta-endorphin), the d (delta) receptor prefers enkephalins, and
the k (kappa) receptor that prefers dynorphins (Goldstein, 1994). Some receptors
are broken down further into subtypes as in the k1 and k2 receptors. A substance
that binds to a receptor is called a ligand, thus endorphins are the natural
ligand for the opiate receptor. The entire endogenous opioid system is referred
to as the “Endogenous Opiate Receptor Ligand System.”
Receptors
have several properties. Any substance, including the endogenous ligand or any
exogenous compound that attaches to a receptor occurs through a
process
of chemical bonding (Goldstein, 1994; Pratt and Taylor, 1990). This kind of
binding to a receptor is referred to as specific. Affinity refers to the
strength that a substance binds to a receptor. Some chemical bonds are stronger
than others resulting in some substances having a greater affinity than others
for a receptor. In respect to opiate receptors and opioid analgesics the
stronger the affinity, the stronger the analgesic properties of the substance.
Therefore, morphine which is a strong analgesic has a stronger affinity for the
opiate receptor than codeine which is a weaker analgesic. Opiate receptors have
been found in every vertebrate and even in some invertebrate species. Therefore,
opiate receptors and the endogenous opioids are basic within the scheme
of evolution. Their vast distribution in species implies that
endorphins were important in the scheme of evolution, and particularly mammalian
(Goldstein, 1994).
Agonists
and Antagonists
An
agonist is a substance that binds to the receptor and produces a response that
is similar in effect to the natural ligand. In contrast, antagonists bind to the
receptor but block it by not allowing the natural ligand or any other compound
to bind to the receptor.
Antagonists
do not cause the opposite effect. They merely fit into the receptor and block
any other substance from binding to it. For example, narcotic antagonists such
as naloxone or its’ predecessor Naline are administered to reverse a heroin or
opioid overdose. This is achieved because opioid antagonists have a greater
affinity for the opiate receptor than agonists and in fact the affinity is so
strong that narcotic antagonists can literally knock an agonist right out of the
receptor. The effect is very fast and the overdose victim will wake up within
minutes, or seconds even. Individuals dependent on heroin, or other opioids such
as methadone can wake up in withdrawal.
Heroin,
methadone and morphine are opioid agonists. Narcotic antagonists are produced by
a change on the nitrogen atom of an opioid agonist. Thus nalorphine is produced
from a change in the nitrogen atom of the morphine molecule and naloxone is
produced from oxymorphone (see Table 1). Naltrexone is a long acting narcotic
antagonist which is used for maintenance treatment. It works by binding to the
receptor over a 24 hour period thus making any injection or administration of an
opioid agonist ineffective. It must be emphasized that naltrexone does not have
agonist properties it merely blocks every opiate receptor irrespective of that
receptors function. Thus, long term treatment with narcotic antagonists can also
block important biological functions and various side effects have been
reported, including hypersexuality.
Methadone
and Congeners
Germany
has been a leader in the discovery and production of pharmaceuticals since the
mid-Nineteenth Century. In the 1850s German scientists discovered the first
molecular structure of a substance, which was morphine.
In the
1930s scientists at I.G. Farbenindustrie (Hoechst-Am-Main) were searching for an
analgesic that would be easier to use during surgery and also have low addiction
potential. In 1937 Max Bockmhl and Gustav Ehrhart discovered a
synthetic substance they called Hoechst 10820 or polamidon and whose structure
had no relation to morphone or the opioid alkaloids (Bockmhl and Ehrhart,
1949). On September
11, 1941 Bockmhl and Ehrhart filed an application for a patent (see Figure 2).
Figure 2.
The Original Patent for Methadone.
(Note: This figure was
scanned from a poor copy and in order to make it readable text was entered that
could be incorrect.)
At the end
of WW2 the town of Hoechst was occupied and the patients of I.G. Farbenindustrie
became property of the U.S. Hoechst 10820 was named methadon and taken to
the Public Health Service Narcotic Treatment Center at Lexington, KY.
Research was conducted in which addicts where found to respond favorably
to it and thus methadone was adopted to withdraw addicts from narcotics (Isbell,
Wikler and Eddy, 1947). However,
methadones properties as a maintenance medication for addicts was not
realized.
For
the next two decades the primary use of methadone was in withdrawing addicts
from narcotics. In the early 1960s Dr. Dole, a metabolic specialist at The
Rockefeller University and Dr. Marie Nyswander, a psychiatrist that specialized
in addiction (Dr. Nyswander could easily be called the first Addiction
Specialist) began research to find a medication that could be used to maintain
addicts. At the start of their research they theorized that addicts would be
better if they could be prescribed a medication instead of purchasing unknown
substance on the illicit market (Dole, 1988).
Unfortunately
their first trial with morphine seemed a failure because their subjects were
still occupied with obtaining their drugs. Since the standard medication to
withdraw addicts was methadone they switched their subjects over to it in
preparation to end the research. However, in an attempt to have something to
show for their work they decided to increase the methadone dose and run the same
tests on their subjects before discharging them from the hospital ward (Anon,
1994). And then something happened!
Their subjects stopped sitting in front of the television waiting for the next
injection; one subject asked that he be allowed to leave the ward to go to work,
one who had never completed high school now also wanted to leave the ward to
return to school, and an other began painting — their subjects began to act
like normal people with interests in things other than drugs.
Dole
and Nyswander soon found that once an adequate treatment dose was reached that
their subjects could be maintained with out needing increases for a prolonged
period of time. Unlike morphine, their subjects on methadone did not need
increasing doses in order to achieve the same effect. They realized that they
had found a maintenance medication.
Dole
and Nyswander underwent another transformation during their initial research.
From their observations they began to postulate that opiate addiction was a
metabolic disease and like the diabetic needing insulin, addicts needed
methadone to maintain normal functions (Dole, 1988). Their ideas were radical
and the Bureau of Narcotics (BON, now the DEA) was threatened by them. The BON
informed Dr. Dole that he was breaking the law and that they would stop his
research unless he ceased it himself. At this point Dr. Dole told a very brave
stance. After obtaining legal advise that their work at The Rockefeller
University was perfectly legal Dr. Dole invited the BON to go ahead and
prosecute him. He also informed the BON that prosecution would create a proper
ruling on the matter. The BON backed down or at least ceased their overt threats
to the project.
Before
we go further lets clear up another myth. Methadone, or Dolophine was not named
after Adolph Hitler. The “dol” in Dolophine comes from the Latin root
“dolor.” The female name Dolores is also derived from it and the term
dol is used in pain research to measure pain e.g., one dol is 1 unit of pain.
Dolophine is the American trade name given to methadone by Eli Lilly during the
1950s.
