Oximes short-acting CB1 receptor agonists
Graphical abstract
Introduction
The endocannabinoid system consists of cannabinoid receptors CB1 and CB2,[1], [2] the endogenous lipid ligands arachidonoylethanolamine (anandamide, AEA)3 and 2-arachidonoylglycerol (2-AG),4 as well as their primary hydrolytic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). The cannabinoid receptors belong to the GPCR family and have very different functions and distributions. The CB1 receptors are widely distributed throughout the brain and mediate the majority of the cannabinoid effects on the central nervous system (CNS).5 In contrast, the CB2 receptors are primarily found in cells of immune origin,6 including microglia, although low-level expression has been reported in healthy neurons.7 The limited successes of cannabinoids as medications in humans relates to the severe psychotropic side-effects which are associated with persistent activation of CB1 receptors in the human brain. Δ9-THC and related synthetic cannabinoids are highly lipophilic molecules, which have the tendency to accumulate in fatty tissues (depot effect) and then being released slowly back into circulation and other body compartments, including the brain.8 As a result, compound accumulation in the lipid-rich environment of the nervous system prolongs the elimination phase of the drug, causing a prolonged activation of CB1 receptors in central compartments with precipitous deleterious side-effects.
Recently, a few examples with synthetic CB1 agonists have been explored to limit the sequestration of the drug in fatty tissues by incorporating hydrophilic esters groups on the molecule. Also, the ester functionality could undergo plasma hydrolysis and generate inactive hydrolytic products, thus shortening the compound’s effect.[9], [10], [11] This approach aimed to limit the prolonged activation of CB1 receptors and minimize the CB1-associated psychotropic side-effects.
In this paper, we have explored two important physicochemical properties hydrophobicity (log P) and topological surface area (tPSA) in drug action, aiming to lower the lipophilic nature of the administered drug and decrease its partition rate in areas rich in fat, especially adipose tissues. We have anticipated our approach to generate new cannabinoids with predictable pharmacokinetics and pharmacodynamic effects, such as onset and duration of drug action. To that end, we have introduced polar moieties at the C3 alkyl tail of Δ8-THC. We have selected the Δ8-THC isomer for our studies based on its superior chemical and thermal stability than Δ9-THC, the principal psychoactive constituent of cannabis. First, we have introduced an “internal” polar oxime moiety at the C3 alkyl tail of Δ8-THC to examine its effect on binding affinity for the cannabinoid receptors CB1 and CB2, and secondly, we have additionally incorporated polar groups at the terminal carbon of the alkyl tail (Fig. 1) to further lower the lipophilic character of the molecule. This design strategy offered the potential to influence the mode of drug action (absorption, distribution and sequestration) and lead to an estimated drug pharmacodynamic effect, comprising of fast onset and projected duration of drug action. We have evaluated selected CB1 agonists in biochemical and in vivo assays, as well as pharmacokinetics studies to assess potency, selectivity and druggabilty.
Section snippets
Chemistry
The reported oximes in this paper were prepared according to synthetic methods A and B.
Results and discussion
All synthesized compounds were tested for their ability to bind to CB1 and CB2 receptors using rat brain17 or HEK293 cell membranes expressing mouse CB2 (mCB2) or human CB2 (hCB2),[18], [19], [20] respectively, via competition-equilibrium binding using [3H]CP-55,940.[19], [20], [21] We used both species (human and mouse) of the CB2 receptors to assess potential affinity differences, which have been previously observed by similar structural chemotypes.22 Our structure-activity relationship (SAR)
Conclusions
In this paper, we have described the synthesis of new short-acting CB1 agonists based on the tricycle-core structure of Δ8-THC in an attempt to “drastically” reduce its lipophilic character, and restrict its tissue sequestration (depot effect), which contributes to a prolonged activation of the CB1 receptor with precipitous psychotropic effects. To that end, we have explored new analogs at the C3-alkyl tail of THC by introducing an “internal” polar oxime and polar groups at the terminal carbon
Funding
This work was supported by The Klarman Family Foundation, Boston, MA [grant number KFF # 3237].
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