(R)-11-hydroxy- and (R)-11-hydroxy-10-methylaporphine: synthesis, pharmacology, and modeling of D2A and 5-HT1A receptor interactions.
(R)-11-Hydroxyaporphine (2) and (R)-11-hydroxy-10-methylaporphine (3) were synthesized from natural morphine by using new, short, and efficient synthetic sequences. The dopaminergic and serotonergic effects of 2 and 3 were evaluated by use of in vitro and in vivo test systems. The results indicate that 3 is a potent, selective, and efficacious 5-HT1A receptor agonist. In contrast, 2 is a partial 5-HT1A receptor agonist of low potency which has affinity also for central D1 and D2A receptors. The differences in pharmacological profiles were rationalized by modeling of ligand-receptor interactions using homology-based receptor models of the 5-HT1A and D2A receptor binding site. The selective and pronounced serotonergic effects of 3 appear to be due to the C10-methyl group, which is accommodated by a lipophilic pocket in the 5-HT1A receptor. In contrast, the C10-methyl group of 3 is not accommodated by the binding site model of the D2A receptor.
Hedberg
M H
MH
Uppsala University, Uppsala Biomedical Centre, Sweden.
Johansson
A M
AM
Nordvall
G
G
Yliniemelä
A
A
Li
H B
HB
Martin
A R
AR
Hjorth
S
S
Unelius
L
L
Sundell
S
S
Hacksell
U
U
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001060:Aporphines / Q000138:chemical synthesis / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D003196:Computer Graphics; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D006801:Humans; D008297:Male; D017551:Microdialysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis / Q000494:pharmacology
D001060:Aporphines; D017448:Receptors, Dopamine D2; D017366:Serotonin Receptor Agonists; C054813:PM 1000; D005576:Colforsin; C007984:11-hydroxyaporphine; D000262:Adenylyl Cyclases