Bot
h of t
he enantiomers of 5-(3-
hydroxyp
henyl)-
N-p
henylet
hylmorp
han wit
h C9
![](/images/gifc<font color=)
hars/alp
ha.gif" BORDER=0>-met
hyl, C9-met
hylene,C9-keto, and C9
![](/images/gifc<font color=)
hars/alp
ha.gif" BORDER=0>- and C9
![](/images/gifc<font color=)
hars/beta2.gif" BORDER=0 ALIGN="middle">-
hydroxy substituents were synt
hesized and p
harmacologically evaluated. T
hreeof t
he 10 compounds, (1
R,5
R,9
S)-(-)-9-
hydroxy-5-(3-
hydroxyp
henyl-2-p
henylet
hyl-2-azabicyclo[3.3.1]nonane ((1
R,5
R,9
S)-(-)-
10), (1
R,5
S)-(+)-5-(3-
hydroxyp
henyl)-9-met
hylene-2-p
henet
hyl-2-azabicyclo[3.3.1]nonane ((1
R,5
S)-(+)-
14), and (1
R,5
S,9
R)-(-)-5-(3-
hydroxyp
henyl)-9-met
hyl-2-p
henet
hyl-2-azabicyclo[3.3.1]nonane ((1
R,5
S,9
R)-(+)-
15)
had subnanomolar affinity at
![](/images/entities/mgr.gif)
-opioid receptors (
Ki = 0.19, 0.19, and0.63 nM, respectively). T
he (1
R,5
S)-(+)-
14 was found to be a
![](/images/entities/mgr.gif)
-opioid agonist and a
![](/images/entities/mgr.gif)
-,
![](/images/gifc<font color=)
hars/delta.gif" BORDER=0 >-, and
![](/images/gifc<font color=)
hars/kappa.gif" BORDER=0 >-antagonistin [
35S]GTP-
![](/images/gifc<font color=)
hars/gamma.gif" BORDER=0 >-S assays and was approximately 50 times more potent t
han morp
hine in a number of acuteand subc
hronic pain assays, including t
hermal and visceral models of nociception. T
he (1
R,5
R,9
S)-(-)-
10compound wit
h a C9-
hydroxy substituent axially oriented to t
he piperidine ring (C9
![](/images/gifc<font color=)
hars/beta2.gif" BORDER=0 ALIGN="middle">-
hydroxy) was a
![](/images/entities/mgr.gif)
-agonistabout 500 times more potent t
han morp
hine. In t
he single-dose suppression assay, it was greater t
han 1000times more potent t
han morp
hine. It is t
he most potent known p
henylmorp
han antinociceptive. T
he molecularstructures of t
hese compounds were energy minimized wit
h density functional t
heory at t
he B3LYP/6-31G*level and t
hen overlaid onto (1
R,5
R,9
S)-(-)-
10 using t
he
heavy atoms in t
he morp
han moiety as a commondocking point. Based on modeling, t
he spatial arrangement of t
he protonated nitrogen atom and t
he 9
![](/images/gifc<font color=)
hars/beta2.gif" BORDER=0 ALIGN="middle">-OHsubstituent in (1
R,5
R,9
S)-(-)-
10 may facilitate t
he alignment of a putative water c
hain enabling protontransfer to a nearby proton acceptor group in t
he
![](/images/entities/mgr.gif)
-opioid receptor.