Oleamide (1) is an endogenous fatty acid primary amide that accumulates in the cerebrospinal fluid under conditions of sleep deprivation and induces physiological sleep in animals (Cravatt et al. (1995) Science 268, 1506-1509; Lerner et al. (1994) Proc. Natl. Acad. Sci. USA 91, 9505-9508; Cravatt et al. (1996) J. Am. Chem. Soc. 118, 580-590). 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 or proposed (Patterson et al. (1996) J. Am. Chem. Soc. 118, 5938-5945; Cravatt et al. (1996) Nature 384, 83-87; Giang et al. Proc. Natl. Acad. Sci. USA 94, 2238-2242; Thomas et al. (1997) J. Neuroscience Res. 50, 1-6; Merkler et al. (1996) Arch. Biochem. Biophys. 330, 430-434).
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 (Koutek et al. (1994) J. Biol. Chem. 269, 22937-22940; Petrocellis et al. (1997) Biochem. Biophys. Rsch. Commun. 231, 82-88; Deutsch et al. (1997) Biochem. Pharmacol. 53, 255-260). The characterization and neuronal distribution of FAAH have been disclosed 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 (Devane et al. (1992) Science 258, 1946-1949; Di Marzo et al. (1995) Prostaglandins, Leukot. Essent. Fatty Acids 53, 1-11). 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.
Recent studies have shown the oleamide modulates serotonergic neurotransmission (Huidobro-Toro et al. (1996) Proc. Natl. Acad. Sci. USA 93, 8078-8082; Thomas et al. (1997) Proc. Natl. Acad. Sci. USA 94, 14115-14119). In the first disclosure of such effects, oleamide was shown to potentiate 5-HT2C and 5-HT2A receptor-mediated chloride currents in transfected frog oocytes, but not those elicited by the 5-HT3 ion-gated channel receptor or other G protein coupled receptors. This potentiation was greatest for the 5-HT2C receptor subtype where the effect was observed at concentrations as low as 1 nM and was maximal at 100 nM oleamide. Oleamide did not alter the serotonin (5-HT) EC50 but instead increased receptor efficacy.
Similarly, oleamide has been reported to potentiate phosphoinositide hydrolysis in rat pituitary P11 cells expressing the 5-HT2 receptor but to inhibit 5-HT7 receptor-mediated stimulation of cAMP levels in HeLa cells transfected with the receptor. In these efforts, oleamide was shown to act as a weak agonist at the 5-HT7 receptor but to behave as an unsurmountable antagonist in the presence of serotonin illustrating that it may act at an allosteric site (Huidobro-Toro et al. (1996) Proc. Natl. Acad. Sci. USA 93, 8078-8082; Thomas et al. (1997) Proc. Natl. Acad. Sci. USA 94, 14115-14119). Thus, oleamide has been shown to enhance (5-HT2A, 5-HT2C), disrupt (5-HT7), or have no effect (5-HT3) on serotonergic signal transduction at various receptor subtypes. Serotonin receptors have been implicated in anxiety, depression, appetite, thermoregulation as well as sleep and mood regulation and strong links between 5-HT1, 5-HT2, and 5-HT7 and the regulation of sleep have been disclosed (Leonard et al. (1996) Psychother. Psychosom. 65, 66-75; Lovenberg et al. (1993) Neuron 11, 449-458).
What is needed are analogs which possess inhanced activity and selectivity over that of oleamide for the potentiation of serotonergic signal transduction at various receptor subtypes.
USPTO Backgrounds
USPTO Backgrounds