Background: SR141716A binds the CB1 receptor selectively and exerts inverse agonist activity. Results: We identify a key role of the minor binding pocket for SR141716A binding. Conclusion: SR141716A exerts inverse agonist activity by securing the Trp rotameric switch, restraining CB1 from activation. Significance: This is the first reported molecular description of the superimposition of SR141716A- and CP55940-binding sites.