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). As it is known that CB 1 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 CB 1 and CB 2 receptors. Structural features required for CB 1/CB 2 affinity and selectivity were explored by molecular modeling. Some compounds in the chromenopyrazole series were observed to be selective CB 1 ligands. These modeling studies suggest that full CB 1 selectivity over CB 2 can be explained by the presence of a pyrazole ring in the structure. The functional activities of selected chromenopyrazoles were evaluated in isolated tissues. Invivo behavioral tests were then carried out 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, thus discounting CNS-mediated effects. This lack of agonistic activity in the CNS suggests that this compound does not readily cross the blood-brain barrier. Moreover, 13a 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 13a in the orofacial test could be mediated through peripheral mechanisms. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Peer Reviewed