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calculated features (see Table S1 in the ESI†). The docked poses
of compounds 8 and 15–17 at FAAH and DRD3 are reported
in the ESI.†
Here, confirming the feasibility of our recently reported
strategy,27 we have combined computational methods and synthetic
efforts to successfully discover novel, potent and balanced dual-
target molecules. The described compounds are an example of dual
modulators rationally designed to display activity toward a GPCR
and an enzyme, which are structurally unrelated but involved in a
common biological function.28 While the vast majority of known
drugs have been developed as selective modulators of a single target,
this approach has shown several limitations in treating complex
and multifaceted pathologies.29 The Multi-Target Directed Ligand
(MTDL) strategy is based on the idea that a single molecular entity
can be devised to hit multiple targets that cooperate in the
framework of the same disease.30 MTDLs may have a superior
therapeutic effect with respect to single target compounds and
might prevent unwanted compensations.31–34 Being able to
modulate DRD3 and inhibit FAAH, this class of compounds
might hold great potential as disease-modifying agents for the
treatment of nicotine addiction.35,36
This work was supported in part by the National Institute for
Drug Abuse Grant No. DP1 DA031387 (to Piomelli). The authors
thank Dr Angelo Reggiani for his comments on the experimental
setup and Dr Giuseppe Giardina for the useful discussions.
Bottegoni, De Simone, Ruda, Bandiera, Piomelli, and Cavalli are
Fig. 2 (a) Docked pose of 7 in the crystal structure of rat FAAH; (b) docked
pose of 7 in the crystal structure of human DRD3.
agonists 2 and 3 for CB1 activity. 3 did not show any activity but inventors in a patent application in which the novel structures
2 turned out to be a rather potent CB1 agonist with an EC50 of described in this study are claimed.
840 nM (Table S1 in the ESI†).
Notes and references
1 B. A. Syed and K. Chaudhari, Nat. Rev. Drug Discovery, 2013, 12,
To design-out CB1 activity, three additional derivatives
were prepared by modifying the O-aryl group according to
Scheme S1 (ESI†).
97–98.
´
´
´
2 J. J. Escobar-Chavez, C. L. Domınguez-Delgado and I. M. Rodrıguez-
Cruz, Drug Des., Dev. Ther., 2011, 5, 211–224.
3 R. Polosa and N. L. Benowitz, Trends Pharmacol. Sci., 2011, 32, 281–289.
4 B. J. Everitt and T. W. Robbins, Nat. Neurosci., 2005, 8, 1481–1489.
5 F. Micheli, ChemMedChem, 2011, 6, 1152–1162.
6 M. Mugnaini, L. Iavarone, P. Cavallini, C. Griffante, B. Oliosi,
C. Savoia, J. Beaver, E. A. Rabiner, F. Micheli, C. Heidbreder,
A. Andorn, E. Merlo Pich and M. Bani, Neuropsychopharmacology,
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7 A. Hackling, R. Ghosh, S. Perachon, A. Mann, H. D. Holtje,
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Since 7 showed a classic partial agonist profile on DRD3 and
a greater selectivity toward DRD2 with respect to 8, the length of
the linker was kept at 4 methylene units. To modulate the
orientation of the aryl-substituent, we introduced a p-biphenyl moiety
(15). Although the latter moiety was reported to be detrimental for
FAAH activity,9 compound 15 maintained a good potency, showed a
partial agonist profile on DRD3, and acquired a small but significant
selectivity ratio over CB1. In this case, the main issue was the selectivity
over DRD2, which, dropping from over 150- to 23-fold, was negatively
affected by this substitution. Next, considering that: (i) 3 is completely
devoid of CB1 activity and that (ii) the naphthyl group was already
reported on both DRD3 modulators5 and FAAH inhibitors,26 the two
naphthyl-substituted regioisomers 16 and 17 were synthesized. These
compounds were endowed with good and balanced activities in the
low nanomolar range. However, 16 did not show any improvement in 10 H. Deng, Expert Opin. Drug Discovery, 2010, 5, 961–993.
11 A. H. Newman, T. Beuming, A. K. Banala, P. Donthamsetti, K. Pongetti,
CB1 selectivity relative to 15, had only a moderate 31-fold selectivity
over DRD2, and the functional assay on DRD3 highlighted an
A. LaBounty, B. Levy, J. Cao, M. Michino, R. R. Luedtke, J. A. Javitch
and L. Shi, J. Med. Chem., 2012, 55, 6689–6699.
almost full agonist activity profile. Conversely, 17 gave successful 12 A. Gaulton, L. J. Bellis, A. P. Bento, J. Chambers, M. Davies,
A. Hersey, Y. Light, S. McGlinchey, D. Michalovich, B. Al-Lazikani
results in the CB1 designing-out effort, showing a good selectivity
and J. P. Overington, Nucleic Acids Res., 2012, 40, D1100–D1107.
with a CB1/DRD3 ratio of over 300-fold and 420 nM EC50 on CB1,
13 X. Min, S. T. Thibault, A. C. Porter, D. J. Gustin, T. J. Carlson, H. Xu,
over 450-fold lower than the prototype 7. Together with potent
and balanced activities (6.1 nM on h-FAAH and 1.3 nM on
DRD3), compound 17 also had 161-fold selectivity over DRD2,
a clear partial agonist profile, and interesting physico-chemical
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and Z. Wang, Proc. Natl. Acad. Sci. U. S. A., 2011, 108, 7379–7384.
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4906 | Chem. Commun., 2014, 50, 4904--4907
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