09.02 Synthesis

The example of a drug that can increase the synthesis of a neurotransmitter is L-DOPA. L-DOPA is used to increase the levels of dopamine, a neurotransmitter in the brain, in Parkinson’s disease. Normal ageing is associated with a loss of dopaminergic neurones (nerves that contain dopamine) in the central nervous system. However, there is a greater loss of dopaminergic neurones in Parkinson’s disease, which was first described by Parkinson. Thus, a 70-80% loss of dopaminergic neurones is associated with Parkinson’s disease.

The clinical syndrome that distinguishes Parkinson’s disease consists of 4 parts. Firstly, there is bradykinesia (which is a slowness/poverty of movement). Secondly, there is muscular rigidity, which makes starting a movement difficult. There may also be resting tremors but these usually stop during voluntary movement. Lastly, there is impairment of balance, with disturbances of gait (movement of limbs) and the subjects with Parkinson’s disease lean forward. Impairment of balance leads to an increased risk of falling.

The main treatment of Parkinson’s disease is to enhance the dopaminergic system. Probably, the most obvious way to enhance the dopaminergic system is to give dopamine. However, dopamine is not active after oral administration as it is metabolised by 2 enzymes (monamine oxidase and catechol-O-methyl transferase), which are found in the gut. To avoid intestinal metabolism, dopamine can be administered intravenously. But, after intravenous administration, dopamine does not cross the blood brain barrier to have central effects. Thus, we cannot use dopamine in Parkinson’s disease.

A very important way to enhance the dopaminergic system is to increase the synthesis of dopamine. L-DOPA is the precursor of dopamine. It is absorbed from the gut on the transporter system for the aromatic amino acids. L-DOPA also gains entry into central nervous system, with transport across the blood brain barrier also being mediated by the transporter for the aromatic amino acids. Once in dopaminergic neurones, L-DOPA is converted to dopamine. When the dopaminergic neurones are activated, the dopamine is released and overcomes the symptoms of Parkinson’s disease.