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.
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