Both of the enantiomers of 5-(3-hydroxypheny
l)-
N-pheny
lethy
lmorphan with C9
![](/images/gifchars/a<font color=)
lpha.gif" BORDER=0>-methy
l, C9-methy
lene,C9-keto, and C9
![](/images/gifchars/a<font color=)
lpha.gif" BORDER=0>- and C9
![](/images/gifchars/beta2.gif)
le">-hydroxy substituents were synthesized and pharmaco
logica
lly eva
luated. Threeof the 10 compounds, (1
R,5
R,9
S)-(-)-9-hydroxy-5-(3-hydroxypheny
l-2-pheny
lethy
l-2-azabicyc
lo[3.3.1]nonane ((1
R,5
R,9
S)-(-)-
10), (1
R,5
S)-(+)-5-(3-hydroxypheny
l)-9-methy
lene-2-phenethy
l-2-azabicyc
lo[3.3.1]nonane ((1
R,5
S)-(+)-
14), and (1
R,5
S,9
R)-(-)-5-(3-hydroxypheny
l)-9-methy
l-2-phenethy
l-2-azabicyc
lo[3.3.1]nonane ((1
R,5
S,9
R)-(+)-
15) had subnanomo
lar affinity at
![](/images/entities/mgr.gif)
-opioid receptors (
Ki = 0.19, 0.19, and0.63 nM, respective
ly). The (1
R,5
S)-(+)-
14 was found to be a
![](/images/entities/mgr.gif)
-opioid agonist and a
![](/images/entities/mgr.gif)
-,
![](/images/gifchars/de<font color=)
lta.gif" BORDER=0 >-, and
![](/images/gifchars/kappa.gif)
-antagonistin [
35S]GTP-
![](/images/gifchars/gamma.gif)
-S assays and was approximate
ly 50 times more potent than morphine in a number of acuteand subchronic pain assays, inc
luding therma
l and viscera
l mode
ls of nociception. The (1
R,5
R,9
S)-(-)-
10compound with a C9-hydroxy substituent axia
lly oriented to the piperidine ring (C9
![](/images/gifchars/beta2.gif)
le">-hydroxy) was a
![](/images/entities/mgr.gif)
-agonistabout 500 times more potent than morphine. In the sing
le-dose suppression assay, it was greater than 1000times more potent than morphine. It is the most potent known pheny
lmorphan antinociceptive. The mo
lecu
larstructures of these compounds were energy minimized with density functiona
l theory at the B3LYP/6-31G*
leve
l and then over
laid onto (1
R,5
R,9
S)-(-)-
10 using the heavy atoms in the morphan moiety as a commondocking point. Based on mode
ling, the spatia
l arrangement of the protonated nitrogen atom and the 9
![](/images/gifchars/beta2.gif)
le">-OHsubstituent in (1
R,5
R,9
S)-(-)-
10 may faci
litate the a
lignment of a putative water chain enab
ling protontransfer to a nearby proton acceptor group in the
![](/images/entities/mgr.gif)
-opioid receptor.