Agonist-antagonist characterization of 6′-cyanohex-2′-yne-Δ8-tetrahydrocannabinol in two isolated tissue preparations

This investigation was directed at characterizing some of the pharmacological properties of 6′-cyanohex-2′-yne-Δ8-tetrahydrocannabinol (O-823), a compound with high affinity for cannabinoid binding sites (Ki = 0.77 nM). In mouse vasa deferentia, O-823 behaved as a potent partial cannabinoid CB1 receptor agonist (EC50 = 0.015 nM). In the guinea-pig myenteric plexus preparation, it antagonized WIN 55,212-2 {(R)-(+)-[2,3-dihydro-5-methyl-3-[4-morpholino)methyl]pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthyl)methanone} and CP 55,940 {(−)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol} with Kd values of 0.65 and 0.27 nM, respectively. After in vivo Δ9-tetrahydrocannabinol pretreatment, the sensitivity of vasa deferentia to O-823-induced inhibition of electrically evoked contractions was reduced by 127-fold. 3.162 nM O-823 was inhibitory in unpretreated vasa deferentia but antagonized CP 55,940 in pretreated tissues (Kd = 0.26 nM). O-823 is probably an antagonist in the myenteric plexus preparation and Δ9-tetrahydrocannabinol pretreated vasa deferentia but a partial agonist in unpretreated vasa deferentia because the first two of these preparations contain fewer receptors than the third.