Structure-Activity Relationship (SAR) of the Phenethylamines: A ...
Structure-Activity Relationship (SAR) of the Phenethylamines: A ...
Structure-Activity Relationship (SAR) of the Phenethylamines: A ...
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Catecholamine Releasers:<br />
Mechanism <strong>of</strong> Action<br />
• An abbreviated (possible) mechanism<br />
• AMP (a weak base) reduces intracellular<br />
pH gradient <strong>of</strong> synaptic vesicles<br />
• Once buffering capacity is exceeded, <strong>the</strong><br />
lack <strong>of</strong> a proton gradient reduces<br />
transmitter uptake driving force<br />
• Deprotonated catecholamine may<br />
diffuse from vesicle along conc gradient<br />
• Elevated cytosolic monoamine may be<br />
released from cell by reversal <strong>of</strong> uptake<br />
pump<br />
Catecholamine Releasers:<br />
<strong>SAR</strong> Summary<br />
Amphetamine Methamphetamine<br />
• Using AMP as <strong>the</strong> model, very little<br />
structural alteration is allowed<br />
• N-CH 3 (METH) increases potency ~2-fold<br />
• S-configuration at α-carbon is preferred<br />
• Assume <strong>the</strong> primary effect <strong>of</strong> interest is<br />
drug-induced efflux <strong>of</strong> neuronal<br />
catecholamines (mostly DA)<br />
• The optimal structure is probably AMP or<br />
METH without aromatic ring substituents<br />
Serotonin Releasers<br />
• Amphetamine is a relatively weak<br />
serotonin releaser<br />
p-Chloroamphetamine<br />
• para-Substitution dramatically increases<br />
neuronal serotonin release<br />
• para-Chloroamphetamine (PCA) is <strong>the</strong><br />
classic example<br />
• para-Chloromethamphetamine received<br />
some clinical attention in <strong>the</strong> early 1970’s<br />
as an antidepressant<br />
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