(R)-(-)-10-methyl-11-hydroxyaporphine: a highly selective serotonergic agonist.
Prior work in these laboratories identified (+/-)-5-hydroxy-6-methyl-2- (di-n-propylamino)tetralin as a dopaminergic agonist prodrug. The ortho methyl hydroxy aromatic substitution pattern in this molecule has now been incorporated into the aporphine ring system to give a congener of the dopaminergic agonist apomorphine in which the position 10 OH group has been replaced by methyl. Preparation of the target compound involved acid-catalyzed rearrangement of the 3-(1-phenyltetrazolyl) ether of morphine and subsequent molecular modification of the product, the 10-(1-phenyltetrazolyl) ether of (R)-(-)-apomorphine. Surprisingly, the target compound elicited no responses in any assays for effects at dopamine receptors, but rather it displayed pharmacological properties consistent with its being a serotonergic agonist with a high degree of selectivity for 5-HT1A receptors similar to the serotonergic agonist 8-hydroxy-2-(di-n-propylamino)tetralin.
Cannon
J G
JG
Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa, Iowa City 52242.
Mohan
P
P
Bojarski
J
J
Long
J P
JP
Bhatnagar
R K
RK
Leonard
P A
PA
Flynn
J R
JR
Chatterjee
T K
TK
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001060:Aporphines / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D002415:Cats; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008968:Molecular Conformation; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000378:metabolism; D013329:Structure-Activity Relationship
D001060:Aporphines; D011985:Receptors, Serotonin; C054813:PM 1000; D012701:Serotonin; D001058:Apomorphine