C-ring cannabinoid lactones: a novel cannabinergic chemotype

Abstract

As a part of our controlled-deactivation ligand development project, we recently disclosed a series of (-)-Δ(8)-tetrahydrocannabinols (THCs) with a metabolically labile ester group at the 2'-position of the side chain. Now, we have replaced the C-ring in the classical THC structure with a hydrolyzable seven-membered lactone. One of the synthesized analogues binds with high affinity to the CB1 receptor (K i = 4.6 nM) and exhibits much lower affinities for the mCB2 and the hCB2. Also, in vitro functional characterization found the compound to be an agonist at rCB1. Consistent with our rational design, the lead cannabinergic lactone identified here is susceptible to metabolic inactivation by plasma esterases, while the respective acid metabolite is inactive at CB receptors. These results are highlighted with molecular modeling of the two regiosomeric lactones.

Keywords: Baeyer−Villiger rearrangement; Cannabinoids; lactones.

Figure 1

Design and enzymatic inactivation of cannabinergic C-ring lactones.

Scheme 1. Synthesis of Cannabinergic C-Ring Lactones

Reagents and conditions: (a) 3, p-TSA, CHCl₃, 0 °C to rt, 72%; (b) TMSOTf, CH₂Cl₂/MeNO₂, 0 °C to rt, 73%; (c) Ac₂O, pyridine, CH₂Cl₂, rt, 90%; (d) m-CPBA, CH₂Cl₂, 0 °C to rt, 97%; (e) LiOH, THF/H₂O, 0 °C, 32–53%; (f) chromatographic separation; (g) CH₃SO₃H, DMAP, toluene, rt, 44%; (h) CH₃SO₃H, DMAP, toluene, rt, 79%.

Chart 1. Structure of the Probable Criegee Intermediate 12 and Rearrangement Pathways Leading to Regioisomeric Lactones 7a and 7b

Figure 2

Lowest energy conformers of the Criegee intermediate 12 in which the peroxide group occupies the equatorial (A, calculated energy: −66.069 kcal/mol) or the axial (B, calculated energy: −67.074 kcal/mol) position of the cyclohexane C-ring. Oxygen atoms are presented in red. Aromatic rings are partially displayed, while hydrogen atoms are not shown. In these almost equienergetic conformers, the C8 carbon is in a position antiperiplanar to the oxygen–oxygen bond of the peroxide (dihedral angle O–O–C9–C8: −177.9° for A and +173.7° for B) and is expected to have a higher migratory aptitude when compared to C10.

Figure 3

Lowest energy conformers for compounds 10 (A) and 11 (B). The C3 dimethylheptyl side chains are partially displayed, while the 1-hydroxyl group is tilted furthest from the viewer. The white grid shows the van der Waals surface for the ester group. The red contours represent the electron density surfaces of the oxygen atoms.