Differential Effects of 2-(Ethylthio)Apomorphine Enantiomers on Striatal Dopamine Overflow in Vivo

Synthesis of 2-Fluoro-11-hydroxy-N-propylnoraporphine: A Potential Dopamine D2 Agonist

“…In addition, it was found that the C-2 position can tolerate a variety of functional substituents without significant effect on the affinity and selectivity at dopamine D 2 receptor . For example, introducing a hydroxyl group at C-2 resulted in compound 2a which displayed potent DA agonist activity although the binding affinity was slightly lower than NPA ( 1b ). 3a-c It was noteworthy that 2-fluoroapomorphine ( 2c ) and its N -propyl analogue ( 2b ), with a more electronegative fluoro substituent at the C-2, showed remarkably high affinity and selectivity at the dopamine D 2 receptor. Compound 2b is among the most potent and selective D 2 agonist synthesized so far with IC 50 of 0.07 nM at D 2 and 1.3 μM at D 1 receptors, respectively 3h.…”

“…For example, introducing a hydroxyl group at C-2 resulted in compound 2a which displayed potent DA agonist activity although the binding affinity was slightly lower than NPA ( 1b ). 3a-c It was noteworthy that 2-fluoroapomorphine ( 2c ) and its N -propyl analogue ( 2b ), with a more electronegative fluoro substituent at the C-2, showed remarkably high affinity and selectivity at the dopamine D 2 receptor. Compound 2b is among the most potent and selective D 2 agonist synthesized so far with IC 50 of 0.07 nM at D 2 and 1.3 μM at D 1 receptors, respectively 3h. Another noteworthy finding was that the 10-hydroxyl group was not a requirement for high dopamine D 2 receptor activity and can be replaced or eliminated.…”

“…Another noteworthy finding was that the 10-hydroxyl group was not a requirement for high dopamine D 2 receptor activity and can be replaced or eliminated. For example, the 10-dehydroxylated analogue 3 (11-OH-NPa) displayed even higher affinity and selectivity for D 2 ( K i = 28 nM) than apomorphine 1a 3i. Further investigation of 3 indicated that, when administered orally, it retained high pharmacological potency and displayed longer duration of action 3i…”

“…For example, the 10-dehydroxylated analogue 3 (11-OH-NPa) displayed even higher affinity and selectivity for D 2 ( K i = 28 nM) than apomorphine 1a 3i. Further investigation of 3 indicated that, when administered orally, it retained high pharmacological potency and displayed longer duration of action 3i 1 Structures of potent aporphine analogues 1a…”

“…The synthesis was initiated from thebaine, which was first N-demethylated followed by realkylation to yield N-propylnorthebaine 7 3g,h Compound 10 was then subjected to a Smiles rearrangement followed by a Schiemann reaction to yield the 2-F-NPA 2b in low yield (25−50%). 3g,h

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