Volume 63, May 2013, Pages 118–132
Biaryl tetrazolyl ureas as inhibitors of endocannabinoid metabolism: Modulation at the N-portion and distal phenyl ring
- Giorgio Ortara,
, 
, - Enrico Moreraa,
- Luciano De Petrocellisb,
- Alessia Ligrestic,
- Aniello Schiano Moriellob,
- Ludovica Moreraa,
- Marianna Nallia,
- Rino Ragnoa, d,
- Adele Pirollia, d,
- Vincenzo Di Marzoc
- a Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, 00185 Roma, Italy
- b Endocannabinoid Research Group, Istituto di Cibernetica, Consiglio Nazionale delle Ricerche, via dei Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy
- c Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, via dei Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy
- d Rome Center for Molecular Design (RCMD), Sapienza Università di Roma, Piazzale Aldo Moro 5, 00185 Roma, Italy
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Abstract
In the present study, we have further extended the structure–activity relationships for the tetrazolyl ureas class of compounds as potential FAAH and/or MAGL inhibitors, by replacing the dimethylamino group of the parent compounds 1 and 2 with bulkier groups or by introducing on the distal phenyl ring of 1 and 2 a selected set of substituents. Some of the new compounds (16, 20, 21, 25, and 28) inhibited FAAH potently (IC50 = 3.0–9.7 nM) and selectively (39- to more than 141-fold) over MAGL, while tetrazole 27 turned out to be a promising dual FAAH–MAGL inhibitor of potential therapeutic use. Covalent docking studies on FAAH indicated that the binding modes of tetrazoles 1–32 did not display a unique pattern. The ability of tetrazoles1–32 to act as TRPV1 and TRPA1 modulators was also investigated.
Graphical abstract
Highlights
Keywords
- Endocannabinoids;
- Fatty acid amide hydrolase (FAAH);
- Monoacylglycerol lipase (MAGL);
- TRPV1 channel;
- TRPA1 channel;
- Biaryl tetrazolyl ureas
Figures and tables from this article:
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Fig. 1.
Structures of compounds LY2318912, 1, and 2.
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Fig. 2.
Structures of carbamoyl tetrazoles synthesized and tested in this study.
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Fig. 3.
Concentration-dependent inhibition of FAAH by compounds 16, 20, 21, 25, 28.
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Fig. 4.
Concentration-dependent inhibition of FAAH by compound 27.
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Fig. 5.
Concentration-dependent inhibition of MAGL by compound 27.
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Fig. 6.
Summary of SARs for tetrazolyl ureas inhibitors of FAAH and/or MAGL.
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Fig. 7.
Examples of the transition state of a co-crystallized inhibitor (A, PDB entry code 3K83) and of that proposed for compound 1 (B) as used in the covalent dockings. The circled arrows indicate the rotatable bonds during the covalent docking.
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Fig. 8.
Binding modes of 1 (magenta) and 2 (blue) regioisomers. In yellow are highlighted the phenyl rings centroids that account for the π–π interaction between Phe192 and the 1 proximal phenyl ring. In wire are also reported the residues in a 5 Å distance from the covalent inhibitors. For sake of clarity hydrogen atoms were undisplayed. Gly240 and Ile242 are depicted in black wire. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
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Fig. 9.
Binding modes of 14 (yellow) and 25 (cyan) regioisomers. In wire are also reported the residues in a 5 Å distance from the covalent inhibitors. For sake of clarity hydrogen atoms were undisplayed. Gly240 and Ile242 are depicted in black wire. For comparison purposes the docked pose for 1 (magenta) is also reported. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
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Scheme 1.
Synthesis of carbamoyl tetrazoles 3–10.
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Scheme 2.
Synthesis of carbamoyl tetrazoles 11–32.
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Table 1.Effect of tetrazoles 1–32 on [14C]AEA hydrolysis by rat brain membranes and [3H]2-AG hydrolysis by COS-7 cell cytosolic fractions.a
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Table 2.Effect of tetrazoles 1–32 on intracellular Ca2+ elevation in HEK293 cells stably transfected with either the human TRPV1 or the rat TRPA1 cDNAs.a
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Table 3.Effect of tetrazole 27 on endocannabinoid levels in intact COS-7 cells.
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