Synthesis and dopamine receptor affinities of enantiomers of 2-substituted apomorphines and their N-n-propyl analogues.
Syntheses of (R)-(-)-2-methoxyapomorphine (R-8), its antipode S-8, and its (R)-(-)-N-n-propyl R-9 derivatives are described. The dopaminergic receptor affinities of these compounds and their 2-unsubstituted counterparts (R)-(-)-apomorphine (R(-)-APO, R-1), (S)-(+)-apomorphine (S(+)-APO, S-1), and (R)-(-)-N-n-propylnorapomorphine (R(-)-NPA, R-2), as well as those of (R)-(-)-2-chloroapomorphine (R(-)-2-Cl-APO, R-6), (R)-(-)-2-bromoapomorphine (R(-)-2-Br-APO, R-6), were determined with tissue membrane preparations of corpus striatum from rat brain. Contribution of both an N-n-propyl and a 2-hydroxy in (R)-(-)-2-hydroxy-N-n-propylnorapomorphine (R(-)-2-OH-NPA, R-7) or a methoxy group in (R)-(-)-2-methoxy-N-n-propylnorapomorphine (R(-)-2-OCH3-NPA, R-9) produced the highest D2 affinity (0.053 and 0.17 nM) and D2 over D1 selectivity (17,300 and 10,500 times) of the compounds evaluated. The structure-affinity relationships of these 2-substituted aporphines suggest that secondary binding sites of D2 receptors interact with 2-substituents on the A ring of aporphines through H-bonding.
Gao
Y G
YG
Section of Medicinal Chemistry, College of Pharmacy and Allied Health Professions, Northeastern University, Boston, Massachusetts 02115.
Baldessarini
R J
RJ
Kula
N S
NS
Neumeyer
J L
JL
D000818:Animals; D001058:Apomorphine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D002417:Cattle; D015259:Dopamine Agents / Q000138:chemical synthesis* / Q000378:metabolism; D007536:Isomerism; D051381:Rats; D011954:Receptors, Dopamine / Q000378:metabolism*
D015259:Dopamine Agents; D011954:Receptors, Dopamine; C064291:2-methoxyapomorphine; C064292:2-methoxy-N-n-propylnorapomorphine; D001058:Apomorphine