CB2-Selective Cannabinoid Receptor Ligands: Synthesis, Pharmacological Evaluation, and Molecular Modeling Investigation of 1,8-Naphthyridin-2(1H)‑one-3-carboxamides

We have recently identified 1,8-naphthyridin-2­(1H)-one-3-carboxamide as a new scaffold very suitable for the development of new CB2 receptor potent and selective ligands. In this paper we describe a number of additional derivatives in which the same central scaffold has been variously functionalize...

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Bibliographic Details
Published in:Journal of medicinal chemistry Vol. 57; no. 21; pp. 8777 - 8791
Main Authors: Lucchesi, Valentina, Hurst, Dow P, Shore, Derek M, Bertini, Simone, Ehrmann, Brandie M, Allarà, Marco, Lawrence, Lyle, Ligresti, Alessia, Minutolo, Filippo, Saccomanni, Giuseppe, Sharir, Haleli, Macchia, Marco, Di Marzo, Vincenzo, Abood, Mary E, Reggio, Patricia H, Manera, Clementina
Format: Journal Article
Language:English
Published: WASHINGTON American Chemical Society 13.11.2014
Amer Chemical Soc
Subjects:
Cell Line, Tumor
Chemistry, Medicinal
Humans
Life Sciences & Biomedicine
Ligands
Models, Molecular
Molecular Docking Simulation
Naphthyridines - chemical synthesis
Naphthyridines - chemistry
Pharmacology & Pharmacy
Receptor, Cannabinoid, CB1 - agonists
Receptor, Cannabinoid, CB2 - agonists
Receptor, Cannabinoid, CB2 - antagonists & inhibitors
Receptor, Cannabinoid, CB2 - chemistry
Science & Technology
Structure-Activity Relationship
SYSTEM
CB2 RECEPTORS
FUNCTIONAL EXPRESSION
1ST POTENT
RHODOPSIN
CREVICE
BINDING
RATIONAL DESIGN
ISSN:0022-2623, 1520-4804, 1520-4804
Online Access:Get full text
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Summary:We have recently identified 1,8-naphthyridin-2­(1H)-one-3-carboxamide as a new scaffold very suitable for the development of new CB2 receptor potent and selective ligands. In this paper we describe a number of additional derivatives in which the same central scaffold has been variously functionalized in position 1 or 6. All new compounds showed high selectivity and affinity in the nanomolar range for the CB2 receptor. Furthermore, we found that their functional activity is controlled by the presence of the substituents at position C-6 of the naphthyridine scaffold. In fact, the introduction of substituents in this position determined a functionality switch from agonist to antagonists/inverse agonists. Finally, docking studies showed that the difference between the pharmacology of these ligands may be in the ability/inability to block the Toggle Switch W6.48(258) (χ1 g+ → trans) transition.
Bibliography:NIH RePORTER
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content type line 23
ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/jm500807e