EVALUATION OF CANNABIMIMETIC EFFECTS OF STRUCTURAL ANALOGS OF ANANDAMIDE IN RATS

Arachidonylethanolamide (anandamide), an endogenous ligand for the can nabinoid receptor, binds competitively to brain cannabinoid receptors and shares many, but not all, of the in vivo effects of Delta(9)-tetra hydrocannabinol. In this study, the cannabinoid effects of anandamide analogs in which the anandamide molecule was altered were assessed in a drug discrimination model. Structural manipulations of the anandamid e molecule included saturation of the arachidonyl moiety with fluorina tion (O-586), substitution for either the ethanolamide moiety (O-612 a nd O-595) or C2' hydroxyl (O-585), and addition of a methyl group at v arious positions (O-610, O-680, and O-689). Despite the low binding af finities of the non-methylated compounds (K-i values > 2000 nM), all o f the analogs had previously shown cannabinoid activity in mice. In th e present study, these analogs were tested in a more pharmacologically specific Delta(9)-tetrahydrocannabinol discrimination procedure in ra ts. This animal model is predictive of the subjective effects of marij uana intoxication in humans. Whereas ag-tetrahydrocannabinol and an am inoakylindole fully substituted for the training dose of 3 mg/kg Delta (9)-tetrahydrocannabinol, anandamide and its non-methylated analogs we re not cannabimimetic in this procedure. Methylation appeared to incre ase binding affinity (K-i values < 150 nM) and efficacy; however, the greatest substitution produced by the methylated analogs occurred only at doses that decreased overall rates of responding, suggesting that these analogs are not fully Delta(9)-tetrahydrocannabinol-like. The ra pid metabolism of anandamide and some of its analogs undoubtedly contr ibute to the differences between the pharmacological profiles of the a nandamides and classical cannabinoids. These results support the predi ction that the subjective effects of anandamide analogs that have been developed thus far would not be cannabimimetic except at high doses. (C) 1998 Elsevier Science B.V. All rights reserved.