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

Abstract

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.

Synthesis, Pharmacological Evaluation, and Docking Studies of Novel Pyridazinone‐Based Cannabinoid Receptor Type 2 Ligands

“…[24] In the current study,G lide docking studies revealed that the novel pyridazinones reported hereb ind in as imilar orientation as the 1,8-naphthyridin-2(1H)-one-3-carboxamides. [24] W6.48 is therefore considered to be part of the "toggle switch"f or activation.A s illustrated in Figure 4B,t he 4-chloro-3-methylphenyl pyridazinone substituent of 22 points towardT MH5 and extends deep enoughi nt he binding pocket to block the movement of W6.48(258) and therefore keep its c1a tg+ .T his is consistent with 22 acting as an inverse agonist at the CB 2 R. Therefore, this docking study provides ar ational structural explanation for the ability of ligandss uch as 22 to preventG -protein-de-pendentCB 2 Ra ctivation. [23][24][25][26] This homology model wasp re-equilibrated in as tearoyl-docosahexaenoylphosphatidylcholine( SDPC) bilayer for 300 ns to allow it to adjust in al ipidic environment [23] (see the Experimental Section).…”

“…Further exploration of the 1,8-naphthyridin-2(1H)-one-3-carboxamide scaffold in the CB 2 RRmodel, showedt hat antagonists from this series bind in the TMH2-3-6-7 region with the C6 naphthyridine substituent directly blockingt he W6.48(258) toggle switch. [24] In the current study,G lide docking studies revealed that the novel pyridazinones reported hereb ind in as imilar orientation as the 1,8-naphthyridin-2(1H)-one-3-carboxamides. The most potent and selectiveC B 2 Ri nverse agonist, 22,w as docked in a previously published CB 2 RR -state model.…”

“…[23] This study suggested that the SR144528 amide functional group is important for interacting with CB 2 R. In addition, aromatic stacking interactions in the transmembrane helix (TMH) 5-6 aromatic cluster werer evealed to be crucial to the SR144528-CB 2 Rc omplex. [23][24][25][26] This homology model wasp re-equilibrated in as tearoyl-docosahexaenoylphosphatidylcholine( SDPC) bilayer for 300 ns to allow it to adjust in al ipidic environment [23] (see the Experimental Section). [24] In the current study,G lide docking studies revealed that the novel pyridazinones reported hereb ind in as imilar orientation as the 1,8-naphthyridin-2(1H)-one-3-carboxamides.…”

“…Here aT rp residue forms an aromatic stacking interaction with Y5.39, influencing the extracellular positions of TMH3-4-5. [23,24,26] Compound 22 was flexibly docked using Glide (version 7.5, Schrçdinger) and the dock with the best Glide score, as ranked by Emodel, was chosen. This CB 2 Rm odel has been tested using results from substituted cysteine-accessibility studies to identify bindingpocket-facing residues, [46,47] from mutation studies of key ligand interactions sites, [46][47][48][49] and from covalent labeling studies of CB 2 R that support al ipid-entry pathway for CB 2 Rl igands.…”

“…The most potent and selectiveC B 2 Ri nverse agonist, 22,w as docked in a previously published CB 2 RR -state model. [23][24][25][26] This homology model wasp re-equilibrated in as tearoyl-docosahexaenoylphosphatidylcholine( SDPC) bilayer for 300 ns to allow it to adjust in al ipidic environment [23] (see the Experimental Section). Ac omplete conformational analysiso f22 was performed to identify the globalm inimum energy conformer as well as other minimum energy conformations that 22 can adopt.…”