Novel pyrazole cannabinoids: Insights into CB1 receptor recognition and activation

Synthesis of an antagonist, SR141716A, that selectively binds to brain cann abinoid (CB1) receptors without producing cannabimimetic activity in vivo, suggests that recognition and activation of cannabinoid receptors are separ able events. In the present study, a series of SR141716A analogs were synth esized and were tested for CB1 binding affinity and in a battery of in vivo tests, including hypomobility, antinociception, and hypothermia in mice. T hese analogs retained the central pyrazole structure of SR141716A with repl acement of the 1-, 3-, 4-, and/or 5-substituents by alkyl side chains or ot her substituents known to impart potent agonist activity in traditional tri cyclic cannabinoid compounds. Although none of the analogs alone produced t he profile of cannabimimetic effects seen with full agonists, several of th e 3-substituent analogs with higher binding affinities showed partial agoni sm for one or more measures. Cannabimimetic activity was most noted when th e 3-substituent of SR141716A was replaced with an alkyl amide or ketone gro up. None of the 3-substituted analogs produced antagonist effects when test ed in combination with 3 mg/kg Delta (9)-tetrahydrocannabinol (Delta (9)-TH C). In contrast, antagonism of Delta (9)-THC's effects without accompanying agonist or partial agonist effects was observed with substitutions at posi tions 1, 4, and 5. These results suggest that the structural properties of 1- and 5-substituents are primarily responsible for the antagonist activity of SR141716A.