Vol. 296, Issue 3, 1013-1022, March 2001

Novel Pyrazole Cannabinoids: Insights into CB₁ Receptor Recognition and Activation

Jenny L. Wiley, Renée G. Jefferson, Mark C. Grier, Anu Mahadevan, Raj K. Razdan and Billy R. Martin

Department of Pharmacology and Toxicology, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, Virginia (J.L.W., R.G.J., B.R.M.); and Organix, Inc., Woburn, Massachusetts (M.C.G., A.M., R.K.R.)

Synthesis of an antagonist, SR141716A, that selectively binds to brain cannabinoid (CB₁) receptors without producing cannabimimetic activity in vivo, suggests that recognition and activation of cannabinoid receptors are separable events. In the present study, a series of SR141716A analogs were synthesized and were tested for CB₁ binding affinity and in a battery of in vivo tests, including hypomobility, antinociception, and hypothermia in mice. These analogs retained the central pyrazole structure of SR141716A with replacement of the 1-, 3-, 4-, and/or 5-substituents by alkyl side chains or other substituents known to impart potent agonist activity in traditional tricyclic cannabinoid compounds. Although none of the analogs alone produced the profile of cannabimimetic effects seen with full agonists, several of the 3-substituent analogs with higher binding affinities showed partial agonism for one or more measures. Cannabimimetic activity was most noted when the 3-substituent of SR141716A was replaced with an alkyl amide or ketone group. None of the 3-substituted analogs produced antagonist effects when tested in combination with 3 mg/kg ⁹-tetrahydrocannabinol (⁹-THC). In contrast, antagonism of ⁹-THC's effects without accompanying agonist or partial agonist effects was observed with substitutions at positions 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.