Novel, potent THC/anandamide (hybrid) analogs

Abstract

The structure activity relationship (SAR) of the end pentyl chain in anandamide (AEA) has been established to be very similar to that of Δ 9 -tetrahydrocannabinol Δ 9 -THC). In order to broaden our understanding of the structural similarities between AEA and THC, hybrid structures 1-3 were designed. In these hybrids the aromatic ring of THC-DMH was linked to the AEA moiety through an ether linkage with the oxygen of the phenol of THC. Hybrid 1 (O-220) was found to have very high binding affinity to CB1 receptors (Ki = 8.5 nM), and it is interesting to note that the orientation of the side chain with respect to the oxygen in the phenol is the same as in THCs. To further explore the SAR in this series the terminal carbon of the side chain was modified by adding different substituents. Several such analogs were synthesized and tested for their CB1 and CB2 binding affinities and in vivo activity (tetrad tests). The details of the synthesis and the biological activity of these compounds are described.

N-Arachidonyl Maleimide Potentiates the Pharmacological and Biochemical Effects of the Endocannabinoid 2-Arachidonylglycerol through Inhibition of Monoacylglycerol Lipase

“…Furthermore, tetrad effects observed with the combination of NAM and 2-AG were significantly attenuated by the CB 1 -selective antagonist SR141716A, but unaffected by the CB 2 -selective antagonist SR144528. These results are consistent with a large body of research demonstrating that cannabinoids of various classes, including AEAs (when metabolism is inhibited), THC-like cannabinoids, bicyclic cannabinoids, and aminoalkylindoles, produce dose-dependent and CB 1 -mediated effects in these tests (Compton et al, 1992a,b; Compton and Martin, 1997; Bourne et al, 2007; Wise et al, 2007). …”

Ligand-specific homology modeling of human cannabinoid (CB1) receptor

“…Licensed drugs target cannabinoid receptors for treating chemotherapy-induced nausea and vomiting, relieving neuropathic pain, and as an appetite stimulant for AIDS patients [4]. Drugs targeting CB1 receptor are continually being developed [5][6][7][8].…”

Improved Enzymatic Procedure for the Synthesis of Anandamide and N‐Fatty Acylalkanolamine Analogues: A Combination Strategy to Antitumor Activity

“…Coupling constants are reported in Hertz [Hz]. 13 C NMR spectra were fully decoupled and are referenced to the middle peak of the solvent CDCl 3 at δ = 77.0 ppm. Splitting patterns are designated as: s, singlet; d, doublet; t, triplet; q, quadruplet; qn, quintet; dd, double doublet, etc.…”

“…[13][14][15] A recent report, based on molecular modelling studies, have shown that FAAH selectively accommodates anandamide into a multipocket binding site and confirmed that the rate of substrate hydrolysis increases with the number of double bonds within the substrate lipid chain. [16] Keeping in mind the above data, we focused on the use of linolenoyl and arachidonoyl derivatives as putative FAAH substrates.…”