Pathophysiology Reveals Drug Targets

A further method employed successfully in classical drug discovery comes from looking at the pathophysiology of a disease. 

In Parkinson disease, Oleg Homykiewitz examined autopsy material from 180 patients and found a huge deficit of dopamine in the basal ganglia. Existing therapy, which is a successful symptom treatment, is to replace this deficit by giving a precursor to the dopamine, L-DOPA. The L-DOPA is converted by the brain into dopamine. Alternatively, one can make artificial dopamines, that is, dopamine receptor agonists, which have a very similar effect on the receptor as natural dopamine. 

These therapeutic approaches were suggested from the original work by Arvid Carlsson. Both approaches provide some degree of relief from tremors and rigidity for 15 to 20 years. Unfortunately, they do not stop or slow the disease, but as symptom treatments they are invaluable. 

Autopsy studies on Alzheimer-afflicted brains some 40 years later showed a similar huge drop in neurotransmitter levels, but this time it was acetylcholine (ACh) in the hippocampus —which is associated with memory. Choline-esterase inhibitors, which stop the breakdown of ACh, were introduced and are presently the only symptom treatment available (Aricept, Excelon, Reminyl, Cognex). Recently, in 2004, memantine was approved as the first treatment to slow progression of Alzheimer s in mild to moderate cases. Work is ongoing to define acetylcholine-like muscarinic M-1 agonists and M-2 agonists that act on acetylcholine receptors directly. 

ViRTUESAND PROBLEMS OF THE Classical Pharmacology Paradigmin Drug Discoveiy 

---