Chromenopyrazoles: Non‐psychoactive and Selective CB₁ Cannabinoid Agonists with Peripheral Antinociceptive Properties

Abstract

The unwanted psychoactive effects of cannabinoid receptor agonists have limited their development as medicines. These CB 1 mediated side effects are due to the fact that CB 1 receptors are largely expressed in the Central Nervous System (CNS). Since it is known that CB 1 receptors are also located peripherally, there is a growing interest in targeting cannabinoid receptors located outside the brain. A library of chromenopyrazoles designed in analogy to the classical cannabinoid cannabinol were synthesized, characterized and tested for cannabinoid activity. Radiolabeled binding assays were used to determine their affinities at CB 1 and CB 2 receptors. Structural features required for CB 1 /CB 2 affinity and selectivity were explored using molecular modeling. Within the chromenopyrazoles series, some of them showed to be selective CB 1 ligands. These modeling studies suggest that CB 1 full selectivity over CB 2 can be accounted for the presence of a pyrazole ring in the structure. The functional activities of selected chromenopyrazoles were evaluated in isolated tissues. Behavioral tests, in vivo, were then carried on the most effective CB 1 cannabinoid agonist (13a). Chromenopyrazole 13a did not induce modifications in any of the tested parameters on the mouse cannabinoid tetrad, discarding CNS-mediated effects. This lack of agonistic activity in the CNS suggests that it does not readily cross the blood-brain barrier.* nadine@iqm.csic.es. Moreover, compound 13a can induce antinociception in a peripheral model of orofacial pain in rat. Taking into account the negative results obtained in the hot plate test, it could be suggested that the antinociception induced by 13a in the orofacial test may be mediated through peripheral mechanisms. NIH Public Access

Chromenopyrazole, a Versatile Cannabinoid Scaffold with in Vivo Activity in a Model of Multiple Sclerosis

“…At the outset, chromanone 4 was prepared by demethylation of the commercially available 5-(1,1-dimethylheptyl)-1,3-dimethoxybenzene ( 1 ) followed by treatment with 3,3-dimethylacrylic acid and α -formylation. 34 …”

Molecular-Interaction and Signaling Profiles of AM3677, a Novel Covalent Agonist Selective for the Cannabinoid 1 Receptor

“…12 Preclinical data suggest an appreciably broader utility for synthetic CB1R agonists as antinociceptive, anti-inflammatory, and anticancer drugs. 13–15 Identification of CB1R functional residues and characterization of ligand-directed information transduction and intracellular trafficking are sought-after to inform the rational, structure-guided design of therapeutically useful CB1R agonists. 16–18 Such information gains particular significance from the proposition that CB1R agonists with specific ligand-binding domains/pharmacological properties might preferentially activate therapeutic signaling cascades over those inviting adverse events, thereby reducing the risk of adverse psychobehavioral responses that may accompany high levels of CB1R activation in the CNS.…”

Involvement of central and peripheral cannabinoid receptors on antinociceptive effect of tetrahydrocannabinol in muscle pain

“…There is a wide literature supporting the efficacy of cannabinoids in craniofacial pain such as trigeminal neuralgia (Liang et al, 2007), orofacial inflammation (Burgos et al, 2010), orofacial muscular pain (Cumella et al, 2012) and orofacial myositis (Niu et al, 2012); but to our knowledge, this study is the first to analyse the antinociceptive effect of THC in acute muscle pain induced by HS.…”