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

The unwanted psychoactive effects of cannabinoid receptor agonists have limited their development as medicines. These CB1-mediated side effects are due to the fact that CB1 receptors are largely expressed in the central nervous system (CNS). As it is known that CB1 receptors are also located peripherally, there is growing interest in targeting cannabinoid receptors located outside the brain. A library of chromenopyrazoles designed analogously to the classical cannabinoid cannabinol were synthesized, characterized, and tested for cannabinoid activity. Radioligand binding assays were used to determine their affinities at CB1 and CB2 receptors. Structural features required for CB1/CB2 affinity and selectivity were explored by molecular modeling. Some compounds in the chromenopyrazole series were observed to be selective CB1 ligands. These modeling studies suggest that full CB1 selectivity over CB2 can be explained by the presence of a pyrazole ring in the structure. The functional activities of selected chromenopyrazoles were evaluated in isolated tissues. In vivo behavioral tests were then carried out on the most effective CB1 cannabinoid agonist, 13?a. Chromenopyrazole 13?a did not induce modifications in any of the tested parameters on the mouse cannabinoid tetrad, thus discounting CNS-mediated effects. This lack of agonistic activity in the CNS suggests that this compound does not readily cross the bloodbrain barrier. Moreover, 13?a can induce antinociception in a rat peripheral model of orofacial pain. Taking into account the negative results obtained with the hot-plate test, the antinociception induced by 13?a in the orofacial test could be mediated through peripheral mechanisms.