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signaling) has recently received a special attention in the
field of GPCRs research (129,131–133). This is due to the
possibility of attaining different therapeutic effects and/or
avoiding untoward effects while targeting the same
receptor protein (134). In this direction, a deeper
functional analysis of the chromepyrazoles reviewed
herein should also be pursued by evaluation of diverse
signaling pathways using different readouts. Functionally
profiling these compounds may lead to fine-tuning the
chromenopyrazole chemotype in order to identify novel
biased agonists of the cannabinoid receptors.
An important step to move forward in the drug
discovery process is to evaluate the pharmacokinetic
profile of the candidates. In silico ADME predictions
suggested that chromenopyrazoles have a favorable
druggability profile, however, in vitro and in vivo data of
the most promising lead compounds is needed to confirm
the pharmacokinetic properties of these novel derivatives.
Albeit more research is clearly needed to continue
towards more preclinical evaluation, the efforts done for
the development of modulators of the ECS based on the
chromenopyrazole heterocycle open new avenues in the
cannabinoid field. Novel pharmacological tools to study
orphan receptors, as well as potential candidates for the
treatment of diverse pathologies can be optimized using
the outstanding starting point provided by the versatile
chromenopyrazole chemotype.
Conflict of interest. The authors state that there are no
conflicts of interest to disclose.
Acknowledgments: Financial support was provided by
Spanish Grants from the Spanish Ministry
MINECO/FEDER and SAF2015-68580-C2. The authors
acknowledge Colegio Oficial de Farmacéuticos de Madrid
and RANF for awarding this work.
8. REFERENCIAS
1 Mechoulam R, Hanus LO, Pertwee R, Howlett AC.
Early phytocannabinoid chemistry to
endocannabinoids and beyond. Nat Rev Neurosci
2014; 15: 757–64.
2 Gaoni Y, Mechoulam R. Isolation, Structure, and
Partial Synthesis of an Active Constituent of Hashish.
J Am Chem Soc 1964; 86: 1646–47.
3 Pertwee RG. Handbook of Cannabis. 1st ed. New
York: Oxford University Press 2014.
4 Silvestri C, Di Marzo V. The Endocannabinoid
System in Energy Homeostasis and the Etiopathology
of Metabolic Disorders. Cell Metab 2013; 17: 475–90.
5 Navarro G, Morales P, Rodríguez-Cueto C,
Fernández-Ruiz J, Jagerovic N, Franco R. Targeting
Cannabinoid CB2 Receptors in the Central Nervous
System. Medicinal Chemistry Approaches with Focus
on Neurodegenerative Disorders. Front Neurosci
2016; 10: 1–11.
6 Pertwee RG, Howlett AC, Abood ME, et al.
International Union of Basic and Clinical
Pharmacology. LXXIX. Cannabinoid Receptors and
180
Paula Morales, Pilar Goya, Nadine Jagerovic
Their Ligands: Beyond CB1 and CB2. Pharmacol Rev
2010; 62: 588–631.
7 Pertwee RG. Emerging strategies for exploiting
cannabinoid receptor agonists as medicines. Br J
Pharmacol 2009; 156: 397–411.
8 Patel S, Hill MN, Cheer JF, Wotjak CT, Holmes A.
The endocannabinoid system as a target for novel
anxiolytic drugs. Neurosci Biobehav Rev 2017; 76:
56–66.
9 Velayudhan L, Van Diepen E, Marudkar M, et al.
Therapeutic potential of cannabinoids in
neurodegenerative disorders: a selective review. Curr
Pharm Des 2014; 20: 2218–30.
10 Watt G, Karl T. In vivo Evidence for Therapeutic
Properties of Cannabidiol (CBD) for Alzheimer’s
Disease. 2017; 8: 1–7.
11 Wilson RI, Nicoll R. Endogenous cannabinoids
mediate retrograde signalling at hippocampal
synapses. Nature 2001; 410: 588–92.
12 Rinaldi-Carmona M, Barth F, Héaulme M, et al.
SR141716A, a potent and selective antagonist of the
brain cannabinoid receptor. FEBS Lett 1994; 350:
240–4.
13 Després J-P, Lemieux I, Alméras N. Contribution of
CB1 blockade to the management of high-risk
abdominal obesity. Int J Obes 2006; 30: 44-52.
14 Price MR, Baillie GL, Thomas A, et al. Allosteric
Modulation of the Cannabinoid CB1 Receptor. Mol
Pharmacol 2005; 68: 1484–95.
15 Lucchesi V, Hurst DP, Shore DM, et al. CB2-
Selective Cannabinoid Receptor Ligands: Synthesis,
Pharmacological Evaluation, and Molecular Modeling
Investigation of 1,8-Naphthyridin-2(1H)-one-3-
carboxamides. J Med Chem 2014; 57: 8777–91.
16 Manera C, Benetti V, Castelli MP, et al. Design ,
Synthesis , and Biological Evaluation of New 1, 8-
Naphthyridin-4(1H)-on-3-carboxamide and Quinolin-
4 (1H)-on-3-carboxamide Derivatives as CB 2
Selective Agonists. Society 2006; 4: 5947–57.
17 Press JB, Birnberg GH. Heterocyclic-fused
benzopyrans as cannabinoid analogues. J Heterocycl
Chem 1985; 22: 561.
18 Cumella J, Hernández-Folgado L, Girón R, et al.
Chromenopyrazoles: non-psychoactive and selective
CB1 cannabinoid agonists with peripheral
antinociceptive properties. ChemMedChem 2012; 7:
452–63.
19 Morales P, Azofra LM, Cumella J, et al. Preparation
of 2 , 2-dimethylchroman-4-ones from 5-alkyl-
substituted resorcinols?: microwave-assisted synthesis
and theoretical calculations. Arkivoc 2014; 2: 319–32.
20 Gong J-P, Onaivi ES, Ishiguro H, et al. Cannabinoid
CB2 receptors: immunohistochemical localization in
rat brain. Brain Res 2006; 1071: 10–23.
21 Van Sickle MD, Duncan M, Kingsley PJ, et al.
Identification and functional characterization of
@Real Academia Nacional de Farmacia. Spain