506
S. Liras et al. / Bioorg. Med. Chem. Lett. 20 (2010) 503–507
Table 2
Binding affinities for delta, mu and kappa receptors and in vitro clearance (HLM) of select 3,3-biaryl-piperidines
Compound
R1
R2
R3
d Ki (nM)
l
Ki (nM)
j
Ki (nM)
Clog P
Clint (ml/min/kg)
89
5a
CONEt2
OH
0.8
35.0
>890
52.0
24.0
>890
66.0
4.1
5b
5c
CONEt2
OH
OH
6.2
2.2
4.9
3.6
113
70
CON(Me)Et
5d
5e
CONEt2
CONEt2
OH
OH
2.9
3.5
>890
>890
24.0
163
3.98
3.48
>300
>300
CF3
S
N
H
N
5f
CONEt2
OH
1.2
>890
>890
2.97
230
N
N
6a
7a
C(OH)Me2
CONEt2
OH
39.0
7
110
41.0
4.30
2.15
22
S
CONH2
>890
>890
NA
heterocyclic aldehydes yielded compounds with high affinity and
excellent selectivity. Trends with amide alkyl substitutions were
similar to those observed for the 4,4 class and consequently we fo-
cused on small amide replacements (e.g., 5c). Tertiary carbinols
replacing the amide moiety delivered compounds with appreciable
affinity for the delta receptor; although the delta receptor affinity
for dimethyl carbinols specifically was lower (e.g., 6a). Replace-
ment of the phenol moiety with a primary carboxamide delivered
compounds which retained similar affinity and selectivity profiles
with the corresponding phenols (e.g., 7a). Clearance, as measured
in vitro by human liver microsomes (HLM) was generally high.
Compounds with small alkyl piperidine nitrogen substitutions
and small amide groups exhibited the better clearance profiles.
Nitrogen substitutions containing heterocyclic moieties did not
improve clearance (e.g., 5e and 5f).
containing heterocyclic moieties (compounds 5e and 7a). Replac-
ing the diethyl amide with carbinols or the phenol with carboxam-
ides in 4,4- and 3,3-biaryl piperidines did not impact the functional
activity.
In conclusion, we have demonstrated that biaryl piperidines are
potent and selective ligands for the delta opioid receptor. We have
been able to identify selective antagonists of the delta opiate
receptor which will aid the pharmacological characterization of
the receptor. While receptor affinity and selectivity can be ratio-
nalized on the basis of the message-address principle, the struc-
tural and conformational requirements that deliver delta receptor
antagonists are subject to additional investigation. Lead com-
pounds from this investigation are generally characterized by high
in vitro clearance. Further progress towards delivering pharmaco-
logical tools with desirable pharmacokinetic properties and char-
acterization of these probes in disease relevant models of ethanol
intake reduction will be disclosed in subsequent reports.
Based on a balance of properties, which included delta receptor
affinity, selectivity and microsomal stability a number of key com-
pounds were characterized for functional activity at the delta
receptor by a GTP-c S assay. Results from the investigation are de-
References and notes
picted in Table 3. Functional activity values included represent the
average of minimally two screening runs. IC50 values are reported
for antagonists. Within the 4,4-biaryl piperidine class good antag-
onists were identified with long aliphatic and branched alkyl
chains (e.g., compounds 1e and 4b). Compounds 1a and 4a with
small aliphatic chains showed significantly reduced functional
activity relative to their binding affinity and this is a phenomenon
we are studying further. Within the 3,3-biaryl piperidine class
good antagonists were identified with small and medium size alkyl
chains (e.g., compounds 5a and 5b) and with larger substitutions
1. (a) Capasso, A. Med. Chem. 2007, 3, 480; (b) Bodnar, R. J. Peptides (Amsterdam,
Netherlands) 2008, 29, 2292.
2. Pacheco, D. F.; Duarte, I. D. G. Eur. J. Pharmacol. 2005, 512, 23.
3. Mendez, M.; Morales-Mulia, M. Curr. Drug Abuse Rev. 2008, 1, 239.
4. Schwyzer, R. Ann. N.Y. Acad. Sci. 1977, 297.
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6. Portoghese, P. S. Trends Pharmacol. Sci. 1989, 10, 230.
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8. Calderon, S. N.; Rothman; Richard, B.; Porreca, F.; Flippen-Anderson, J. L.;
McNutt, R. W.; Xu, H.; Smith, L. E.; Bilsky, E. J.; Davis, P.; Rice, K. C. J. Med. Chem.
1994, 37, 2125.
9. Dondio, G.; Ronzoni, S.; Eggleston, D. S.; Artico, M.; Petrillo, P.; Petrone, G.;
Visentin, L.; Farina, C.; Vecchietti, V.; Clarke, G. D. J. Med. Chem. 1997, 40, 3192.
10. Mitch, C. H.; Leander, J. D.; Mendelsohn, L. D.; Shaw, W. N.; Wong, D. T.;
Cantrell, B. E.; Johnson, B. G.; Reel, J. K.; Snoddy, J. D.; Takemori, A. E.;
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Table 3
Delta receptor functional activity for representative biaryl piperidines
11. Dolle, R. E.; Schmidt, S. J.; Kruse, L. J. Chem. Soc., Chem. Commun. 1987, 904.
12. Selnick, H. G.; Smith, G. R.; Tebben, A. J. Synth. Commun. 1995, 25, 3255.
13. McMaster, L.; Langreck, F. B. J. Am. Chem. Soc. 1917, 39, 103.
14. All compounds were characterized by 1H NMR and mass spectroscopy and
gave satisfactory spectral data. For example, Compound 4a: 1H NMR (400 MHz,
CDCl3) d 7.71 (t, J = 1.8 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.38–7.22 (m, 6H), 6.09
(br, 1H), 5.83 (br, 1H), 2.61–2.40 (m, 7H), 2.15–2.13 (m, 2H), 1.94 (br, 1H),
1.81–1.73 (m, 5H), 0.82–0.78 (m, 1H), 0.71 (t, J = 7.5 Hz, 6H), 0.48–0.40 (m, 2H),
0.04–0.01 (m, 2H); MS (M+1) 421.2.Compound 4b: 1H NMR (400 MHz, CDCl3) d
7.76 (t, J = 1.66 Hz, 1H), 7.50 (ddd, J = 7.76, 1.41, 1.17 Hz, 1H), 7.39–7.16 (m,
6H), 6.00 (br, 1H), 5.71 (br, 1H), 3.45 (s, 1H), 2.44 (br, 7H), 1.99 (dd, J = 19.42,
Compound
d IC50 (nM)
1a
1e
4a
4b
5a
5b
5e
7a
155
72
282
4.7
7.1
55
16
12