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The chromenopyrazole scaffold in the modulation of the endocannabinoid system: a broad therapeutic prospect

Scheme 1. Synthesis of chromenopyrazoles. Reaction conditions: (i) BBr3, CH2Cl2, overnight, 0 ºC-r.t.; (ii) 3,3-
dimethylacrylic acid, methanesulfonic acid, P2O5, 8 h, 70 ºC, (iii) a) NaH, THF, MW, 25 min, 45 ºC; b) ethyl formate, MW,
25 min, 45 ºC; (iv) corresponding hydrazine, EtOH, 1-4 h, 40 ºC. R1: pentyl or 1,1-dimethylheltyl; R2: hydrogen, methyl,
ethyl, or dichlorophenyl (18).

Briefly, these compounds were prepared from the revealed that among the lipophilic alkyl chains tested at
resorcinol (2) previously obtained after demethylation of R1, aliphatic pharmacophoric position in
the corresponding 1,3-dimethoxybenzene (1) with boron phytocannabinoids, the 1,1-dimethylheptyl group is clearly
tribromide. Chromanone 3 was obtained by treatment of preferred. Pentyl alkyl side chains lead to weaker binders
the resorcinol with 3,3-dimethylacrylic acid in presence of or compounds that do not have affinity at all for these
phosphorous pentoxide (19). Subsequent a–formylation of receptors. However, the 1,1-dimethylheptyl analogues
the chromanones under microwave conditions using display significant to high affinity and selectivity for CB1R
sodium hydride followed by the addition of ethyl formate (CB1R Ki: 4.5–28.5 nM; CB2R Ki: >40000 nM). In what
yielded 4. Finally, condensation of the ß-ketoaldehyde (4) concerns the substitution on the pyrazole ring or the nature
with the appropriate hydrazine gave the N1- and N2- of the R2 substituents, the affinity values remained similar
substituted chromenopyrazoles regioisomers (5 and 6) with among 1,1-dimethylheptyl analogues (18). Figure 3
different relative ratios. summarizes the structural features of this series of
compounds in relation to their cannabinoid receptor
The synthesized compounds were evaluated in vitro for affinity.
their ability to displace the radioligand [3H]CP55,940 from
human CB1R and CB2R (18). These affinity binding assays

Figure 3. Summary of chromenopyrazole structural features related to CBR affinity.

Mouse vas deferens functional assays were performed the cannabinoid mouse tetrad. This in vivo behavioral test
with the compounds that exhibit higher binding affinities indicates if a compound has CNS-mediated effects.
(7, 8a, and 8b, figure 4). These chromenopyrazoles Compound 8a did not induce modifications in any of the
inhibited the electrically evoked contractile response of tetrad parameters at doses up to 10 mg/kg which indicates
this tissue confirming their agonistic properties (18). The that it is not acting in the brain, and thus, not readily
most potent and effective agonist (8a) was then tested in crossing the blood–brain barrier.

@Real Academia Nacional de Farmacia. Spain 167