Structural requirements for 5-HT _2A and 5-HT _1A serotonin receptor potentiation by the biologically active lipid oleamide

Abstract

Oleamide is an endogenous fatty acid primary amide that possesses sleep-inducing properties in animals and that has been shown to effect serotonergic receptor responses and block gap junction communication. Herein, the potentiation of the 5-HT 1A receptor response is disclosed, and a study of the structural features of oleamide required for potentiation of the 5-HT 2A and 5-HT 1A response to serotonin (5-HT) is described. Of the naturally occurring fatty acids, the primary amide of oleic acid (oleamide) is the most effective at potentiating the 5-HT 2A receptor response. The structural features required for activity were found to be highly selective. The presence, position, and stereochemistry of the ⌬ 9 -cis double bond is required, and even subtle structural variations reduce or eliminate activity. Secondary or tertiary amides may replace the primary amide but follow a well defined relationship requiring small amide substituents, suggesting that the carboxamide serves as a hydrogen bond acceptor but not donor. Alternative modifications at the carboxamide as well as modifications of the methyl terminus or the hydrocarbon region spanning the carboxamide and double bond typically eliminate activity. A less extensive study of the 5-HT 1A potentiation revealed that it is more tolerant and accommodates a wider range of structural modifications. An interesting set of analogs was identified that inhibit rather than potentiate the 5-HT 2A , but not the 5-HT 1A , receptor response, further suggesting that such analogs may permit the selective modulation of serotonin receptor subtypes and even have opposing effects on the different subtypes.Oleamide (1) is an endogenous fatty acid primary amide that accumulates in the cerebrospinal fluid under conditions of sleep deprivation (1-3) and induces physiological sleep in animals (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) is an integral membrane protein that degrades 1 to oleic acid, and potent inhibitors of the enzyme have been detailed (4, 9-11). The characterization and neuronal distribution of FAAH have been disclosed (5-7), and the enzyme was found to possess the ability to hydrolyze a range of fatty acid amides including anandamide, which serves as an endogenous ligand for the cannabinoid receptor (12, 13). Unlike anandamide, an appealing feature 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 peptide hormones terminating in a primary amide (8).Recent studies have shown the oleamide modulates serotonergic neurotransmission (14,15). In the first disclosure of such effects, oleamide was shown to potentiate 5-HT 2C and 5-HT 2A receptor-mediated chloride currents in transfected frog oocytes but not those elicited by the 5-HT 3 ion-gated channel recepto...

Altered responsiveness of serotonin receptor subtypes following long-term cannabinoid treatment

“…Biochemical work has suggested that endocannabinoids may enhance 5-HT 1A receptor-mediated responses but attenuate 5-HT 2A receptor-mediated responses (Boger et al, 1998), a finding partially supported by behavioural studies demonstrating that acutely, cannabinoid administration can reduce 5-HT 2A receptor-mediated behavioural responses (Cheer et al, 1999 ;Darmani, 2001 ;Gorzalka et al, 2005). The effects of acute administration of cannabinoid ligands on 5-HT 1A receptor-mediated behavioural responses remain to be determined.…”

Potent and Selective α-Ketoheterocycle-Based Inhibitors of the Anandamide and Oleamide Catabolizing Enzyme, Fatty Acid Amide Hydrolase

“…2,4 In a structurally specific manner, it was found to modulate serotonergic systems [21][22][23] and GABAergic transmission, 24,25 block glial gap junction cell-cell communication, 26,27 decrease body temperature and locomotor activity, 28 and exhibit the characteristic in vivo analgesic and cannabinoid behavorial effects of anandamide, 21,29 albeit without direct cannabinoid receptor activation. It has been suggested that the cannabinoid behavorial effects of oleamide (1b) may be mediated through an as yet unknown distinct pharmacological target.…”

Comparative Characterization of a Wild Type and Transmembrane Domain-Deleted Fatty Acid Amide Hydrolase: Identification of the Transmembrane Domain as a Site for Oligomerization

“…Anandamide (arachidonoyl ethanolamide) was first characterized as an endogenous brain ligand for the CB1 cannabinoid receptor (15) and has since been shown to possess cannabinoid-like properties in vivo (19). Oleamide (9-Z-octadecenamide) was isolated from the cerebrospinal fluid of sleep-deprived cats (20), found to induce physiological sleep when injected into rats (14), and shown to modulate 5-hydroxytryptamine (5-HT) receptor responses to serotonin (21)(22)(23). FAAH is highly expressed in neurons within the central nervous system where the enzyme appears poised to inactivate fatty acid amides at their presumed sites of action (24,25).…”