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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Vydáno v:	Journal of medicinal chemistry Ročník 57; číslo 21; s. 8777 - 8791
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	WASHINGTON American Chemical Society 13.11.2014 Amer Chemical Soc
Témata:	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
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Popis
Shrnutí:	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.
Bibliografie:	NIH RePORTER ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804 1520-4804
DOI:	10.1021/jm500807e