EVIDENCE THAT METHYL ARACHIDONYL FLUOROPHOSPHATE IS AN IRREVERSIBLE CANNABINOID RECEPTOR ANTAGONIST

1 Methyl arachidonyl fluorophosphonate (MAFP) (1 mu M) significantly a ttenuated the ability of WIN 55,212-2, CP 55,940, (-)-Delta(9)-tetrahy drocannabinol (THC), nabilone and (R)-(+)-arachidonoyl-1'-hydroxy-2'-p ropylamide (methanandamide) to inhibit electrically-evoked isometric c ontractions of the myenteric plexus-longitudinal muscle preparation of guinea-pig small intestine, 2 The sizes of the maximal responses to W IN 55,212-2 and CP 55,940 decreased significantly in the presence of 1 mu M MAFP. 3 MAFP (1 mu M) essentially abolished the inhibitory effec ts on the twitch response of the highest concentration of methanandami de used (3.162 mu M). The dextral shift it induced in the log concentr ation-response curve of nabilone was non-parallel. In contrast, the de xtral shift in the log concentration-response curve of THC produced by MAFP did not deviate significantly from parallelism and was relativel y small with a mean value of 3.45 and 95% confidence limits of 1.19 an d 13.08. 4 MAFP (1 mu M) did not attenuate the effects of normorphine or clonidine on the twitch response of the myenteric plexus-longitudin al muscle preparation or affect the contractile response of this prepa ration to acetylcholine. 5 When administered by itself at concentratio ns of I to 1000 nM, MAFP had no detectable effect on the twitch respon se of the myenteric plexus-longitudinal muscle preparation. 6 These re sults support the hypothesis that MAFP is an irreversible cannabinoid CB1 receptor antagonist that possesses some degree of selectivity.