Evidence that methyl arachidonyl fluorophosphonate is an irreversible cannabinoid receptor antagonist.

Abstract

1. Methyl arachidonyl fluorophosphonate (MAFP) (1 microM) significantly attenuated the ability of WIN 55,212-2, CP 55,940, (-)-delta 9-tetrahydrocannabinol (THC), nabilone and (R)-(+)-arachidonoyl-1'-hydroxy-2'-propylamide (methanandamide) to inhibit electrically-evoked isometric contractions of the myenteric plexus-longitudinal muscle preparation of guinea-pig small intestine. 2. The sizes of the maximal responses to WIN 55,212-2 and CP 55,940 decreased significantly in the presence of 1 microM MAFP. 3. MAFP (1 microM) essentially abolished the inhibitory effects on the twitch response of the highest concentration of methanandamide used (3.162 microM). The dextral shift it induced in the log concentration-response curve of nabilone was non-parallel. In contrast, the dextral shift in the log concentration-response curve of THC produced by MAFP did not deviate significantly from parallelism and was relatively small with a mean value of 3.45 and 95% confidence limits of 1.19 and 13.08. 4. MAFP (1 microM) did not attenuate the effects of normorphine or clonidine on the twitch response of the myenteric plexus-longitudinal muscle preparation or affect the contractile response of this preparation to acetylcholine. 5. When administered by itself at concentrations of 1 to 1000 nM, MAFP had no detectable effect on the twitch response of the myenteric plexus-longitudinal muscle preparation. 6. These results support the hypothesis that MAFP is an irreversible cannabinoid CB1 receptor antagonist that possesses some degree of selectivity.