Joseph Knoll’s reply to Lary Stein’s Comment on his work
I am thankful for your comments so rich in ideas. Let me just pick out the PEA problem which still deserves special attention. Thousands of papers have described and analyzed this trace amine in the mammalian brain classified as a releaser of catecholamines. Owing to the synthesis of amphetamine and methamphetamine, the long-acting PEA-derivatives in the 1930s, these compounds played a key role as special stimulants of the catecholaminergic brain engine. However, light was thrown only in the mid 1990s on the fact that PEA is primarily an endogenous catecholaminergic activity enhancer (CAE) substance and in very high concentrations only a releaser of catecholamines. Amphetamine and methamphetamine are PEA-derived CAE substances which, like their parent compound, are releasers of catecholamines. The CAE effect of PEA and the amphetamines remained undetected for decades because the catecholamine releasing effect concealed their detectability. Only the synthesis of (-)-deprenyl, the first PEA-derivative devoid of the catecholamine releasing property, made the CAE effect clearly visible. (-)-Deprenyl, still known as the first selective inhibitor of B-type MAO, blocks this enzyme in the brain of rats in a subcutaneous dose of 0.25 mg/kg and exerts its specific CAE effect in a subcutaneous dose of 0.001 mg/kg. (-)-Deprenyl paved the way for the development of (-)-BPAP, the most selective and most potent synthetic enhancer substance known, which stimulates enhancer-sensitive neurons in femto/picomolar concentrations and is the ideal pharmacological tool to detect hitherto unknown enhancer regulations in the mammalian brain. It is my ardent wish to provoke discussion of enhancer regulation, considering all angles of the question, and to move scientists to examine closely the soundness of the available data. I count upon your aid in this undertaking and I thank you for your appreciation of my work.
November 6, 2014