Medicinal Chemistry

Withdrawal symptoms can be immediately precipitated in addicts by the administration
of narcotic antagonists.

5.18.6 Biochemical Effects of Opiate Hormones

Since they are linked to G-proteins, opioid receptors affect intracellular Ca2+and protein
phosphorylation. Another principal biochemical effect of opiates is the inhibition of
adenylate cyclase (AC), which decreases cAMP production.
Hypotheses concerning the mechanisms of tolerance, addiction, and withdrawal
symptoms are based on adaptive syndromes. In tolerance without dependence, recep-
tors become uncoupled from the Giunit of the receptor complex, and higher doses are
necessary to produce analgesia. When dependence develops, the chronic deficit of
cAMP triggers a compensatory feedback loop to rectify the low cAMP levels, which are
due to inhibition of AC (i.e., its low turnover number). Compensation can be achieved
either by an increased synthesis of new AC molecules or, perhaps, by an increase in
turnover number of the existing AC. The consequently increased amount of AC will,
even in its inhibited state, produce sufficient cAMP to meet all of the requirements for
the cells. In this condition, the organism will function normally onlyin the presence of
opiate, and physiological habituation results. When the level of opiate drops, either
because of drug withdrawal or through the administration of an antagonist, the previ-
ously inhibited AC produces cAMP at a normal rate; the concentration of AC increases
to higher than normal levels, causing a sudden flood of cAMP; this triggers the multi-
ple and diffuse withdrawal symptoms, which may even prove fatal.
It is proper to distinguish between habituation and addiction. The former is a
biochemical–physiological process, whereas the latter has very considerable psycho-
logical and socioeconomic components as well.

5.18.7 Pharmacological Effects of Opiate Hormones

Although the pharmacological activity of the endorphins and enkephalins is analgesic,
the endorphins have a wider range of effects. Among other effects, they induce cata-
tonic rigidity in animals, which is reversible by opiate antagonists. The hope of con-
necting endorphins to schizophrenia was not fulfilled; nor was the expectation of
finding the ideal, nonaddicting analgesic among these peptides. Strangely, and unfortu-
nately, repeated doses of endorphin or enkephalin give rise to addiction and withdrawal
symptoms. There are indications that acupuncture analgesia operates through
enkephalin mobilization, since it is reversed by opiate antagonists.

5.18.8 Opium Alkaloids

Opium alkaloids are nonpeptide agonists for the opioid peptide hormone receptors. The
dried latex of Papaver somniferum(opium), or the seed capsule of the plant itself,
are the sources of almost 25 alkaloids. Some simple isoquinolines from opium, like
papaverine (5.86), are antispasmodics. The principal alkaloid (~10% of the total) is
morphine (3.11), which is also an isoquinoline (rings C and E) but can additionally be
considered a phenanthrene derivative (rings A, B, and C).

354 MEDICINAL CHEMISTRY