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available membrane preparation under conditions previ-
ously described for the NOP receptor.12 The activity of
the mu agonist DAMGO was used for data normaliza-
tion (maximal effect elicited by 10lM DAMGO =
100%; background GTPcS binding in the absence of
agonist = 0%).
groups at the 3-position of the 3,3-diphenylpropyl tail
group. The SAR for the 3-substitution effects indicates
that groups like amides and esters will increase the mu
affinity while an acidic group will decrease the mu affin-
ity. In addition, we have also evaluated the impor-
tance of the basic nitrogen on the piperidine ring by
introducing the N-oxide group. The lack of affinity of
these N-oxides towards the mu receptor is consistent
with previous findings about the antidiarrheal agent lop-
eramide oxide.14 The SAR trends described in this paper
may allow a better understanding of mu receptor recog-
nition for the 4-phenylpiperidine mu ligands. The thera-
peutic potential of these loperamide analogs may also be
of interest for the scientific community in light of our re-
cent discovery of DiPOA, a novel, systemically available
and peripherally restricted mu opioid agonist with anti-
hyperalgesic activity.15,16
Table 1 shows the results from mu and NOP receptor
binding and functional assays for the compounds de-
scribed above. In general, these compounds show better
affinity towards the mu receptor than the NOP receptor.
A number of compounds have shown subnanomolar
affinities against mu while only a few compounds pos-
sess ꢀ100nM affinities for the NOP receptor. The sub-
stitution patterns on the 4-phenyl ring have certain
effects on the ligandsÕ affinities towards mu receptor,
which is evidenced by compounds 1A–C with a rank
order of 3-CF3 (1nM) > 3-CF3, 4-Cl (4nM) > 4-Cl
(37nM). However, this 4-phenyl ring substitution effect
is reduced to a negligible level with tail groups such as
N,N-dimethyl-2,2-diphenylbutyramide group and 2,2-
diphenylbutyric acid methyl ester group. For example,
compounds 8A–9C have affinities ranging from 0.11 to
0.53nM. It is interesting that the N-1 substitutions have
a dramatic effect on the affinity of the ligand. For com-
pounds 2CI–2CIII, the 4-cyano substitution on the
phenylmethyl tail group resulted in an inactive com-
pound, while the 4-trifluoromethyl analog binds with
an affinity of 104nM and the 2-naphthylmethyl analog
binds with an affinity of 2.5nM. This comparison of
the tail group also illustrates another SAR trend within
this series, which is the 3-substitution effect at the 3,3-
diphenylpropyl tail group. Changing from a hydrogen
(1A–C) to N,N-dimethylamide group (8A–C) or 3-meth-
oxycarbonyl group (9A–C) dramatically increased the
mu affinities ranging approximately from 6-fold (1A vs
8A) to 4000-fold (1C vs 8C). These amide and ester
groups may serve three purposes: (1) a polar function
capable of hydrogen bonding with an electrophilic site
(or amino acid residues) in the mu receptor; (2) steric
interaction with the two phenyl groups causing them
to take a better orientation to interact more effectively
with the mu receptor; (3) hydrophobic interaction with
a small pocket in the mu receptor. It is also interesting
to see that a carboxylic acid group at the 3-position of
the 3,3-diphenylpropyl tail group (compounds 10A–C)
lowers the ligandÕs affinity for mu receptor (331, 1461
and 489nM, respectively). This indicates that the small
pocket in the mu receptor cannot tolerate an acidic
group.
Acknowledgements
We thank Drs. Sam F. Victory, John Whitehead, R.
Richard Goehring, Jeffrey M. Marra for suggestions
and helpful discussions.
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