AM630, A COMPETITIVE CANNABINOID RECEPTOR ANTAGONIST

AM630 (iodopravadoline), a novel aminoalkylindole, has been found to a ttenuate the ability of a number of cannabinoids to inhibit electrical ly-evoked twitches of the mouse isolated vas deferens. It did not bloc k the inhibitory effects of morphine or clonidine on the twitch respon se. AM630 behaved as a competitive antagonist of CP 55,940, WIN 55,212 -2, anandamide and (R)-(+)-arachidonyl-1'-hydroxy-2'-propylamide (AM35 6), producing rightward shifts in the log concentration response curve s of these cannabinoid receptor agonists that were concentration-depen dent, essentially parallel and not accompanied by any decrease in the size of maximal response. AM630 also produced concentration-dependent, parallel rightward shifts in the log concentration-response curve of Delta(9)-THC. However, these shifts were accompanied by a decrease in the maximal response. AM630 was markedly more potent as an antagonist of Delta(9)-THC and CP 55,940 (K-d = 14.0 and 17.3 nM respectively) th an as an antagonist of WIN 55,212-2, AM356 or anandamide (K-d = 36.5, 85.9 and 278.8 nM respectively). These differences in dissociation con stant imply that the mouse vas deferens may contain more than one type of cannabinoid receptor. The data also indicate that the receptors fo r which AM630 has the highest affinity may not be CB1 cannabinoid rece ptors as the CB1 selective antagonist, SR141716A, is known to be equal ly potent in attenuating the inhibitory effects of CP 55,940 and anand amide on the twitch response of the mouse vas deferens.