Pharmacological and behavioral evaluation of alkylated anandamide analogs

Adams, Irma B.; Ryan, William J.; Singer, M. I. C.; Razdan, Raj K.; Compton, David R.; Martin, Billy R.

doi:10.1016/0024-3205(95)00187-b

Cited by 72 publications

(50 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, oleyl propanolamide exhibited comparable properties. Thus, the hydroxyl group of oleyl ethanolamide (25)(26)(27)(28)(29)(30)(31). In contrast, the bis-(ethanol)amides were ineffective at inhibiting the gap junction at 50 M, which is consistent with their behavior as bulky tertiary amides that exhibit lower activity.…”

Section: Resultssupporting

confidence: 56%

“…From these studies, which were assisted with the inclusion of the primary amides of nonnaturally occurring fatty acids, a clear depiction of the structural requirements of the endogenous agent emerged. The effective inhibitors of the gap junction-mediated dye transfer fall into two classes of which oleamide and arachidonamide (9)(10)(11)(25)(26)(27)(28)(29)(30)(31)(32) are the prototypical members.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Chemical requirements for inhibition of gap junction communication by the biologically active lipid oleamide

Boger

Patterson

Guan

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

125

View full text Add to dashboard Cite

Oleamide is an endogenous fatty acid primary amide that possesses sleep-inducing properties in animals and has been shown to effect serotonergic systems and block gap junction communication in a structurally specific manner. Herein, the structural features of oleamide required for inhibition of the gap junction-mediated chemical and electrical transmission in rat glial cells are defined. The effective inhibitors fall into two classes of fatty acid primary amides of which oleamide and arachidonamide are the prototypical members. Of these two, oleamide constitutes the most effective, and its structural requirements for inhibition of the gap junction are well defined. It requires a chain length of 16-24 carbons of which 16-18 carbons appears optimal, a polarized terminal carbonyl group capable of accepting but not necessarily donating a hydrogen bond, a ⌬ 9 cis double bond, and a hydrophobic methyl terminus. Within these constraints, a range of modifications are possible, many of which may be expected to improve in vivo properties. A select set of agents has been identified that serves both as oleamide agonists and as inhibitors of fatty acid amide hydrolase, which is responsible for the rapid inactivation of oleamide.Oleamide (1) is an endogenous fatty acid primary amide shown to accumulate in the cerebrospinal fluid under conditions of sleep deprivation (1-3). In a structurally specific manner, it has been shown to induce physiological sleep in animals when administered by i.p. or i.v. injection (1). Consistent with its role as a prototypical member of a new class of biological signaling molecules, enzymatic regulation of the endogenous concentrations of oleamide has been described (1, 4-7) or proposed (8). Fatty acid amide hydrolase (FAAH, oleamide hydrolase) is an integral membrane protein that degrades 1 to oleic acid, and potent inhibitors (K i ϭ 13 M-1 nM) of the enzyme have been detailed (4). The characterization and neuronal distribution of FAAH have been disclosed (5-7), and it was found to possess the capabilities of hydrolyzing a range of fatty acid amides including anandamide, which serves as an endogenous ligand for cannabinoid receptors (9-11). In contrast to anandamide, an appealing feature of the members of this new class of biological signaling agents is the primary amide, suggesting that their storage and release may be controlled in a manner analogous to that of short peptide hormones and messengers terminating in a primary amide (8).In addition to its sleep-inducing properties in animals, oleamide has been shown to effect serotonergic systems (7,(12)(13)(14) and to block gap junction communication (15) in a structurally specific manner. Although it was found to inhibit the gap junction-mediated chemical and electrical transmission in rat glial cells, it had no inhibitory effect on mechanically stimulated or glutamate-induced calcium wave propagation, thereby decoupling two previously indistinguishable glial cell communication pathways (15). Given the central role of intercellular chemic...

show abstract

Section: Resultssupporting

confidence: 56%

Section: Resultsmentioning

confidence: 99%

Chemical requirements for inhibition of gap junction communication by the biologically active lipid oleamide

Boger

Patterson

Guan

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

125

View full text Add to dashboard Cite

show abstract

“…These compounds included an array of commonly used ligands for cannabinoid receptors and a number of analogs of both anandamide and WIN55212-2. This included: anandamide and 2-arachidonyl glycerol, ⌬ 9 -THC, ⌬ 8 -THC, cannabinol, cannabidiol, HU-210, HU-211, CP55940, CP55244, SR141716A, SR144528, the anandamide analogs 1Ј-methyl-anandamide (O-610), 2-methyl-anandamide (O-680), 2-dimethyl-anandamide (O-687) (Adams et al, 1995b), 2-methylarachidonyl-(2Ј-fluoroethyl)amide (O-689) (Adams et al, 1995a), WIN55212-2 (and several analogs: JWH-030, JWH-031, JWH-032, JWH-036, JWH-044, JWH-045, and JWH-073) (Wiley et al, 1998). The only compounds that produced statistically significant dose-dependent stimulation of [ 35 S]GTP␥S binding in CB 1…”

Section: Stimulation Of [ 35 S]gtp␥s Binding By Various Compoundsmentioning

confidence: 99%

Evidence for a New G Protein-Coupled Cannabinoid Receptor in Mouse Brain

Breivogel

Griffin²,

Marzo³

et al. 2001

Mol Pharmacol

Self Cite

520

336

View full text Add to dashboard Cite

The purpose of these studies was to support the hypothesis that an undiscovered cannabinoid receptor exists in brain. [(35)S]GTP gamma S binding was stimulated by anandamide and WIN55212-2 in brain membranes from both CB(1)(+/+) and CB(1)(-/-) mice. In contrast, a wide variety of other compounds that are known to activate CB(1) receptors, including CP55940, HU-210, and Delta(9)-tetrahydrocannabinol, failed to stimulate [(35)S]GTP gamma S binding in CB(1)(-/-) membranes. In CB(1)(-/-) membranes, SR141716A affected both basal and anandamide- or WIN55212-2-induced stimulation of [(35)S]GTP gamma S binding only at concentrations greater than 1 microM. In CB(1)(+/+) membranes, SR141716A inhibited only 84% of anandamide and 67% of WIN55212-2 stimulated [(35)S]GTP gamma S binding with an affinity appropriate for mediation by CB(1) receptors (K(B) approximately 0.5 nM). The remaining stimulation seemed to be inhibited with lower potency (IC(50) approximately 5 microM) similar to that seen in CB(1)(-/-) membranes or in the absence of agonist. Further experiments determined that the effects of anandamide and WIN55212-2 were not additive, but that the effect of mu opioid, adenosine A1, and cannabinoid ligands were additive. Finally, assays of different central nervous system (CNS) regions demonstrated significant activity of cannabinoids in CB(1)(-/-) membranes from brain stem, cortex, hippocampus, diencephalon, midbrain, and spinal cord, but not basal ganglia or cerebellum. Moreover, some of these same CNS regions also showed significant binding of [(3)H]WIN55212-2, but not [(3)H]CP55940. Thus anandamide and WIN55212-2 seemed to be active in CB(1)(-/-) mouse brain membranes via a common G protein-coupled receptor with a distinct CNS distribution, implying the existence of an unknown cannabinoid receptor subtype in brain.

show abstract

“…Thus, the insertion of two methyl groups in the a-position of AA-EG provides hydrolytic stability but does not dramatically influence binding properties, yet eliminates the characteristic effects on behavior. Interestingly, the same modifications in anandamide molecule also resulted in the formation of a stable and potent CB 1 ligand, which was also active in behavioral tests (Adams et al, 1995). Thus one could suggest the involvement of different receptor subtypes in the physiological effects of endocannabinoid amides and esters and their methyl-derivatives.…”

Section: Discussionmentioning

confidence: 94%

“…Recent studies have revealed that methylation of AEA in the a-position of the acyl chain provided very potent and stable cannabimimetic compounds (Adams et al, 1995). In the present work, we investigated the pharmacological properties of two ester EC analogs: arachidonoylethyleneglycol (AA-EG) and a,a,-dimethyl arachidonoylethyleneglycol (DMA-EG).…”

Section: Introductionmentioning

confidence: 99%