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. 2024 May 28;15(6):965-971.
doi: 10.1021/acsmedchemlett.4c00175. eCollection 2024 Jun 13.

Chiral Me-2-arachidonoyl Glycerols: The First Potent Endocannabinoid Glyceride Templates with Stability to COX-2

Spyros P Nikas  1 , Lipin Ji  1 , Yingpeng Liu  1 , Markos-Orestis Georgiadis  1 , Amey Dopeshwarkar  2 , Alex Straiker  2 , Shalley Kudalkar  3 , Anastasiia V Sadybekov  4 , Michaela Dvorakova  2 , Vsevolod Katritch  4 , Ken Mackie  2 , Lawrence Marnett  3 , Alexandros Makriyannis  1   5
Affiliations

Chiral Me-2-arachidonoyl Glycerols: The First Potent Endocannabinoid Glyceride Templates with Stability to COX-2

Spyros P Nikas et al. ACS Med Chem Lett. .

Abstract

2-Arachidonoyl glycerol (2-AG) is the principal endogenously produced ligand for the cannabinoid CB1 and CB2 receptors (CBRs). The lack of potent and efficacious 2-AG ligands with resistance against metabolizing enzymes represents a significant void in the armamentarium of research tools available for studying eCB system molecular constituents and their function. Herein we report the first endocannabinoid glyceride templates with remarkably high potency and efficacy at CBRs. Two of our lead chiral 2-AG analogs, namely, (13S)- and (13R)-Me-2-AGs, potently inhibit excitatory neurotransmission via CB1 while they are endowed with excellent resistance to the oxidizing enzyme COX-2. Our SAR results are supported by docking studies of the key analog and 2-AG on the crystal structures of CB1.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
(a) Structures and pharmacophoric regions (blue boxes) of AEA (1a) and 2-AG (1b). (b) Design of novel chiral 2-AG probes.
Scheme 1
Scheme 1. Chemoenzymatic Synthesis of Chiral Me-2-AGs 2a–d
Reagents and conditions: (a) 9, DMAP, EDCI, CH2Cl2, 0 °C to rt, overnight, 92–95%; (b) resin-immobilized lipase B from Candiada antarctica, anhydrous EtOH, rt, 2 h, 49–53%; (c) resin-immobilized lipase B from Candida antarctica, CH2Cl2, 0 °C, 5 h, 98%.
Figure 2
Figure 2
Concentration-dependent curves of inhibition of forskolin-stimulated cAMP accumulation at rat CB1 (A, B) and mCB2 (C, D) for 2-AG, 2-AG analogs, and standard CP55,940.
Figure 3
Figure 3
(a) Oxygenation of arachidonic acid (AA), 2-AG and key analogs by mCOX-2. The oxygen consumption was monitored using an oxygen electrode chamber as described in the experimental section in Supporting Information. (b) 2-AG, AM8125 (2a), and AM8146 (2b) all potently and efficaciously inhibit excitatory neurotransmission via CB1. EPSC: excitatory postsynaptic currents.
Figure 4
Figure 4
Predicted docking poses of 2-AG (A) and AM8125 (B) in the AM841-bound CB1 receptor binding pocket (PDB code 5xr8). 2-AG is shown as yellow sticks. AM8125 is shown as orange sticks with the (13S)-Me circled black. CB1 receptor helices and residues are shown in blue.
Figure 5
Figure 5
Predicted docking poses of 2-AG (A) and AM8125 (B) in the AMG315-bound CB1 receptor binding pocket (PDB code 8ghv). 2-AG is shown as yellow sticks. AM8125 is shown as orange sticks with the (13S)-Me circled black. CB1 receptor helices and residues are shown in tan.
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