Cannabinoid properties of methylfluorophosphonate analogs

Methylarachidonylfluorophosphonate (MAFP) and related analogs have been sho wn to inhibit fatty acid amidohydrolase activity (FAAH), the enzyme respons ible for hydrolysis of the endogenous cannabinoid ligand anandamide. To ful ly characterize this class of compounds, methylfluorophosphonate compounds with saturated alkyl chains ranging from C8 to C20 along with C20 unsaturat ed derivatives were synthesized and evaluated for their ability to interact with the CB1 receptor, inhibit FAAH, acid produce in vivo pharmacological effects. These analogs demonstrated widely varying affinities for the CB1 r eceptor. Of the saturated compounds, C8.0 was incapable of displacing [H-3] CP 55,940 binding, whereas C12:0 exhibited high affinity (2.5 nM). The C20: 0 saturated analog had low affinity (900 nM), but the introduction of unsat uration into the C20 analogs restored receptor affinity. However, none of t he analogs were capable of fully displacing [H-3]CP 55,940 binding. On the other hand, all compounds were able to completely inhibit FAAH enzyme activ ity, with the C20:0 analog being the least potent. The most potent FAAH inh ibitor was the short-chained saturated C12:0, whereas the other analogs wer e 15- to 30-fold less potent. In vivo, the C8.0 and C12:0 analogs were high ly potent and fully efficacious in producing tetrahydrocannabinol (THC)-lik e effects, whereas the other analogs were either inactive or acted as parti al agonists. None was capable of attenuating the agonist effects of THC. Co nversely, the C20:0 analog potentiated the effects of anandamide but not th ose of 2-arachidonoyl-glycerol and THC. The high in vivo potency of the nov el short-chain saturated MAFP derivatives (C8:0 and C12.0) underscores the complexity of manipulating the endogenous cannabinoid system.