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Paula Morales, Pilar Goya, Nadine Jagerovic

Scheme 2. Synthesis of 5-alkyl-2-(1H-pyrazol-5-yl)benzene-1,3-diols. Reagents and solvents: Route A: (i) AlCl3, acyl
chloride, CH2Cl2; (ii) NaH, ethyl formate, MW; (iii) Hydrazine, ethanol; (iv) NaH, 3- bromo-2-methylpropene; (v) Br3B,
CH2Cl2. Route B: i) AlCl3, acyl chloride, CH2Cl2; ii) Perchloric acid, triethyl orthoformate ; iii) Hydrazine, ethanol.

This work shows that the chromenopyrazole Even though CB1R/CB2R agonists are currently in the
experience inspired the design of 5-alkyl-2-(1H-pyrazol- forefront of clinical research (120) for different
5-yl)benzene-1,3-diols. So far, two synthetic routes have applications such as epilepsy (Epidiolex®), cancer and
been proposed. With these compounds, the possibility of neuroprotection, there is an increasing interest in
overcoming the psychotropic side effects related to ?9- exploiting novel pharmacological strategies (121). For
THC still need to be confirmed before pharmacological instance, CB2R selective agonists or peripherally
prospection. restricted CB1R/CB2R agonists may exhibit therapeutic
potential for treating various pathologies while avoiding
7. SUMMARY AND FUTURE PERSPECTIVES the adverse psychotropic effects related to the modulation
The potential of cannabinoid receptor ligands has of CB1R in the brain (122). In addition, CB1R and/or
CB2R antagonists or inverse agonist as well as allosteric
been preclinically explored in the treatment of diverse cannabinoid ligands which are coming on the scene, may
symptoms and diseases such as pain, inflammation, be useful in the treatment of certain diseases (121,123).
metabolic syndromes, cancer, hypertension, bone-related Nonetheless, more preclinical and specially clinical
disorders or neurodegenerative processes. However, just research needs to be done in this field.
a few of these diseases can be treated with cannabinoid-
based medicines nowadays. Marinol® (dronabinol, In this context, the chromenopyrazole scaffold
synthetic ?9-THC) and Cesamet® (nabilone, a THC emerges as a privileged structure in drug discovery
synthetic analogue) can be prescribed in several countries targeting the endocannabinoid system. Several papers
as antiemetic drugs for chemotherapy-induced nausea have been published describing the synthesis, the
and vomiting (35,36), and for anorexia (119) treatment in pharmacological and biological properties of
patients with AIDS. Sativex® (nabiximols, a combination chromenopyrazoles and derivatives. The first
of ?9-THC and CBD, 1:1 ratio) is used for the chromenopyrazoles, described in 1985, did not show
symptomatic relief of neuropathic pain in adults suffering significant activity in a neuroleptic evaluation. The
multiple sclerosis, and as an adjunctive analgesic discovery of the endocannabinoid system and specially
treatment for adult cancer patients. Rimonabant the cannabinoid receptors, allowed exploring this
(SR141716A), a CB1R antagonist/inverse agonist, was scaffold as cannabinoid ligand. Structural modifications
commercialized in Europe in 2006 as Acomplia® for the on the chromenopyrazole core allowed the development
management of obesity (13). Unfortunately, the of cannabinoid drugs with a broad therapeutic prospect.
beneficial effects were accompanied by a significantly
increase of depression, anxiety, headache, and suicidal Strategies pursued so far in this field have been
thoughts which forced its withdrawal from the market summarized in figure 15. Phenolic chromenopyrazole
few years later. derivatives were claimed in 2012 as non-psychoactive
and selective CB1R agonists with peripheral
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@Real Academia Nacional de Farmacia. Spain