With prolonged administration, L-DOPA causes undesirable involuntary movements.
Moreover, after 4–5 years, Parkinson’s patients tend to become resistant to L-DOPA;
this resistance occurs because the neurons required to convert the L-DOPA to dopamine
are gradually dying off during the progression of the disease. This deficiency of
dopamine transmission in the brain may be compensated by using ergot derivatives
(e.g., bromocriptine (4.87), lisuride (4.100), cabergoline (4.101), pergolide (4.102)) or
nonergot compounds (e.g., ropinirole (4.103), pramipexole (4.104)). These compounds
are direct agonists for dopamine receptors and do not require conversion of L-DOPA to
dopamine. These direct agonists stimulate various dopamine receptors (D1, D2 , D3)
and share similar adverse effects to L-DOPA. Drugs that possibly mobilize DA stores,
like amantadine (4.79), are sometimes of some use in treating certain forms of
Parkinson’s disease. Another potential mechanism of action for amantadine may
involve blockade of ligand-gated ion channels of the NMDA type, ultimately leading to
diminished release of acetylcholine. Since Parkinson’s disease is not only a deficiency
of dopamine but also an alteration in the dopamine/acetylcholine concentration ratio
within the brain, anticholinergic agents may be of value. Clinically, anticholinergics are
better for the suppression of the tremor of Parkinson’s disease, whereas the dopaminer-
gics are better for the bradykinesia (slow movements).
Another approach to the therapy of Parkinson’s disease involves the use of enzyme
inhibitors. For example, inhibition of the enzyme monoamine oxidase B (MAO-B) by
selegiline (4.105) improves the duration of L-DOPA therapy because it inhibits the
breakdown of dopamine but not of NE. Likewise, inhibitors of catechol-O-methyl-
transferase (COMT) can also be exploited as agents for the treatment of Parkinson’s
disease. L-DOPA and dopamine become inactivated by methylation; the COMT
enzyme responsible for this metabolic transformation can be clocked by agents such as
entacapone (4.106) or tolcapone (4.107), allowing higher levels of L-DOPA and
dopamine to be achieved in the corpus striatum of the brain.
248 MEDICINAL CHEMISTRY