homo-gamma-linolenylethanolamide and anandamide

Topics: Amides; Amidohydrolases; Amines; Animals; Arachidonic Acids; Binding Sites; Cannabinoid Receptor Modulators; Drug Design; Endocannabinoids; Esters; Ethers; Glycerides; Humans; Ligands; Monoacylglycerol Lipases; Polyunsaturated Alkamides; Receptors, Cannabinoid

In order to establish the structural requirements for binding to the brain cannabinoid receptor (CB1), we have synthesized numerous fatty acid amides, ethanolamides, and some related simple derivatives and have determined their Ki values. A few alpha-methyl- or alpha, alpha-dimethylarachidonoylalkylamides were also examined. In the 20:4, n-6 series, the unsubstituted amide is inactive; N-monoalkylation, at least up to a branched pentyl group, leads to significant binding. N,N-Dialkylation, with or without hydroxylation on one of the alkyl groups, leads to elimination of activity. Hydroxylation of the N-monoalkyl group at the omega carbon atom retains activity. In the 20x, n-6 series, x has to be either 3 or 4; the presence of only two double bonds leads to inactivation. In the n-3 series, the limited data reported suggest that the derived ethanolamides are either inactive or less active than comparable compounds in the n-6 series. Alkylation or dialkylation of the alpha carbon adjacent to the carbonyl group retains the level of binding in the case of anandamide (compounds 48, 49); however, alpha-monomethylation or alpha,alpha-dimethylation of N-propyl derivatives (50-53) potentiates binding and leads to the most active compounds seen in the present work (Ki values of 6.9 +/- 0.7 to 8.4 +/- 1.1 nM). We have confirmed that the presence of a chiral center on the N-alkyl substituent may lead to enantiomers which differ in their levels of binding (compounds 54, 57 and 55, 56).

Topics: Amides; Animals; Arachidonic Acids; Brain; Endocannabinoids; Ethanolamines; Magnetic Resonance Spectroscopy; Molecular Structure; Polyunsaturated Alkamides; Protein Binding; Rats; Receptors, Cannabinoid; Receptors, Drug; Structure-Activity Relationship; Synaptosomes

In this study we examined whether tolerance develops to chronic exposure to anandamides [20:4, n-6 (ANA) and 20:3, n-6 (HLEA)] two of the recently discovered endogenous cannabinoid receptor ligands in brain. Tolerance to ANA and cross-tolerance to delta 9-tetrahydrocannabinol (delta 9-THC) was examined in female Sabra or C57BL/6 mice which had received daily injections (i.p.) of low (0.001-1 mg/kg) or high doses (20 mg/kg) of ANA or HLEA for 2 weeks. Twenty four h after the last injection, the mice were challenged with 20 mg/kg ANA or delta 9-THC. Animals were subjected to a series of tests frequently used to assess cannabinoid-induced effects. The results indicated that the high dose, but not the low doses of anandamides produced tolerance to ANA and cross-tolerance to delta 9-THC for motor activity in an open field, catalepsy on a ring, hypothermia and analgesia on a hot plate. One week after the last ANA treatment, tolerance was not present anymore. No tolerance to ANA was observed for reduced defecation in the open field, a measure of intestinal hypomotility. This phenomenon may possibly be attributed to a difference between activities produced through different types of cannabinoid receptors.

Topics: Animals; Arachidonic Acids; Dose-Response Relationship, Drug; Dronabinol; Drug Tolerance; Endocannabinoids; Ethanolamines; Fatty Acids, Unsaturated; Female; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Polyunsaturated Alkamides; Receptors, Cannabinoid; Receptors, Drug; Time Factors