STRUCTURE-ACTIVITY-RELATIONSHIPS FOR CANNABINOID RECEPTOR-BINDING ANDANALGESIC ACTIVITY - STUDIES OF BICYCLIC CANNABINOID ANALOGS

Cannabimimetic compounds, such as DELTA9-tetrahydrocannabinol (DELTA9- THC), evoke analgesia in addition to other behavioral responses in hum ans and animals. The cannabinoid receptor mediating this response has been characterized by its ability to bind the cannabinoid agonist [H-3 ]CP-55,940 and to inhibit adenylyl cyclase via G(i). An investigation of structural requirements for antinociceptive activity of cannabinoid structures led to the development of a simple bicyclic cannabinoid ag onist, CP-47,497, that possessed a spectrum of cannabinoid activities in animals that resembled that of DELTA9-THC. The present investigatio n examines several series of CP-47,497 analogs for their binding affin ity at the cannabinoid receptor and their ability to evoke analgesia i n rodents. Analogs substituted at the C-3 alkyl side chain exhibited m aximal affinity for the cannabinoid receptor with side chains of seven or eight carbons in length. Analgesic potency paralleled the receptor -binding affinity. The cyclohexyl ring was optimized as a six- or seve n-membered ring structure for binding as well as analgesic activity. C yclohexyl alkyl side chain extensions of up to four carbons in length had little influence on the affinity for the receptor or analgesic act ivity. Hydroxyalkyl side chains exhibited optimal binding affinity and antinociceptive activity at three or four carbon atoms in length; how ever, polar groups closer to the ring diminished binding to the recept or. The importance of the phenolic and cyclohexyl hydroxyl groups for binding affinity was demonstrated. In general, analgesic activity corr elated well with the affinity of these analogs for the cannabinoid rec eptor. Exceptions could be explained by metabolic transformations like ly to occur in vivo.