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The chromenopyrazole scaffold in the modulation of the endocannabinoid system: a broad therapeutic prospect
structures that can be classified in 11 families: ?9-THC, should be exempt of the undesirable psychotropic effects
?8-THC, cannabigerol (CBG), cannabichromene (CBC), related to the activation of brain CB1R to have greater
cannabidiol (CBD), cannabinodiol (CBND), cannabielsoin opportunity to be explored as cannabinoid-based
(CBE), cannabicyclol (CBL), cannabinol (CBN), and medicines.
cannabitriol (CBT), miscellaneous-type cannabinoids.
Whereas ?9-THC is the most abundant and main Numerous cannabinergic ligands have been described
psychoactive constituent of cannabis, CBD, the second thus far. Besides the phytocannabinoids previously
most abundant, is a non-psychotropic substance (3). detailed, other modulators of the cannabinoid receptors
However, ?9-THC has attracted much attention since its proceeding from endogenous or synthetic sources have
discovery. Thus, a considerable amount of been identified. These compounds present very different
pharmacological studies was done on its activity chemical structures and pharmacological profiles.
supporting its value as therapeutic agent and that, before
the discovery of the endocannabinoid system (ECS). Endogenous cannabinoids, endocannabinoids,
comprise a family of polyunsaturated fatty acids that
Over the past three decades, the ECS has emerged as a structurally differ from phytocannabinoids. These
promising therapeutic target. Two G-protein coupled molecules, are lipid neurotransmitters that mediate
receptors (GPCRs), the cannabinoid receptors type 1 retrograde signal from postsynaptic neurons to presynaptic
(CB1R) and type 2 (CB2R), and their endogenous lipid ones targeting CBRs (11). Among the most abundant
ligands were identified in the 1990s as the main endocannabinoids identified so far are anandamide [N-
constituents of the ECS. CB1R is highly expressed in the arachidonoylethanolamine (AEA), figure 1], and 2-
central nervous system (CNS) modulating numerous arachidonoylglycerol (2-AG, figure 1).
physiological processes such as cognition, emotion or pain
control. This receptor is also localized in the peripheral In addition, the interest gained by the ECS as valuable
tissue (liver, kidney, or lung among others) where it target for drug discovery led to the synthesis of numerous
modulates energy balance and metabolism (4). On the cannabinoid ligands in the last years. The development of
other hand, CB2R is mainly expressed in the immune synthetic endocannabinoid and phytocannabinoid
system, the gastrointestinal tract and in certain neuronal analogues, as well as chemically diverse scaffolds, offered
subpopulations. Interestingly, the expression of CB2R in novel pharmacological opportunities in this field. Among
the CNS is upregulated upon neuroinflammatory stimuli, the most remarkable synthetic cannabimimetics discovered
what confers to this receptor an important role in the are the well-known aminoalkyindole R-(+)-WIN55,212-2
treatment of neurodegenerative disorders (5). (figure 1), and the synthetic phytocannabinoid CP55,940
(figure 1). Both of them are very potent CB1R/CB2R
The orphan receptors GPR18 and GPR55 have also agonists that have been extensively used to investigate the
been proposed as potential members of the ECS (6). endocannabinoid system. Another compound that has
Unfortunately, the current lack of pharmacological tools to significantly contributed to the understanding of the
study these receptors is delaying the understanding of their cannabinoid receptors is the arylpyrazole SR141716A
relation with the cannabinoids. (Rimonabant, figure 1) (12). This compound is a potent
CB1R antagonist/inverse agonist which therapeutic
It is widely demonstrated that compounds targeting the potential was confirmed for the management of obesity
ECS have therapeutic potential for the clinical (13), however, it also triggers undesired side effects.
management of an ever growing number of disorders (7).
These include inflammatory and neuropathic pain, Other classes of ligands that exhibit interesting
neurological pathologies, metabolic syndrome, or cancer cannabinoid activity have also been developed by
among others (8–10). The only cannabinoids on clinical pharmaceutical companies and academic research groups.
use today are the phytocannabinoids ?9-THC and CBD, For instance, indole-2-carboxamides, such as the CB1R
and the ?9-THC synthetic derivative nabilone, which are allosteric modulator ORG27569 (14), or CB2R ligands
approved for pain, emesis and appetite disorders. Taking derived from the 1,8-naphthyridine-3-carboxamide
into account the fact that these compounds lack of scaffold (15,16), were developped.
CB1R/CB2R selectivity, identifying new synthetic selective
cannabinoids is of great interest. These novel entities
@Real Academia Nacional de Farmacia. Spain 165
