The endogenous lipid signaling agent oleoylethanolamide (OEA) has recently been described as a peripherally acting agent that reduces food intake and body weight gain in rat feeding models. This paper presents evidence that OEA is an endogenous ligand of the orphan receptor GPR119, a G protein-coupled receptor (GPCR) expressed predominantly in the human and rodent pancreas and gastrointestinal tract and also in rodent brain, suggesting that the reported effects of OEA on food intake may be mediated, at least in part, via the GPR119 receptor. Furthermore, we have used the recombinant receptor to discover novel selective small-molecule GPR119 agonists, typified by PSN632408, which suppress food intake in rats and reduce body weight gain and white adipose tissue deposition upon subchronic oral administration to high-fat-fed rats. GPR119 therefore represents a novel and attractive potential target for the therapy of obesity and related metabolic disorders.
Background and purpose: Rimonabant (Acomplia TM , SR141716A), a cannabinoid CB 1 receptor inverse agonist, has recently been approved for the treatment of obesity. There are, however, concerns regarding its side effect profile. Developing a CB 1 antagonist with a different pharmacological mechanism may lead to a safer alternative. To this end we have screened a proprietary small molecule library and have discovered a novel class of allosteric antagonist at CB 1 receptors. Herein, we have characterized an optimized prototypical molecule, PSNCBAM-1, and its hypophagic effects in vivo. Experimental approach: A CB 1 yeast reporter assay was used as a primary screen. PSNCBAM-1 was additionally characterized in [ 35 S]-GTPgS, cAMP and radioligand binding assays. An acute rat feeding model was used to evaluate its effects on food intake and body weight in vivo. Key results: In CB 1 receptor yeast reporter assays, PSNCBAM-1 blocked the effects induced by agonists such as CP55,940, WIN55212-2, anandamide (AEA) or 2-arachidonoyl glycerol (2-AG). The antagonist characteristics of PSNCBAM-1 were confirmed in [ 35 S]-GTPgS binding and cAMP assays and was shown to be non-competitive by Schild analyses. PSNCBAM-1 did not affect CB 2 receptors. In radioligand binding assays, PSNCBAM-1 increased the binding of [ 3 H]CP55,940 despite its antagonist effects. In an acute rat feeding model, PSNCBAM-1 decreased food intake and body weight. Conclusions and implications: PSNCBAM-1 exerted its effects through selective allosteric modulation of the CB 1 receptor. The acute effects on food intake and body weight induced in rats provide a first report of in vivo activity for an allosteric CB 1 receptor antagonist.
The hypothalamic peptide orexin-A and the orexin-1 receptor are localized in areas of the brain and spinal cord associated with nociceptive processing. In the present study, localization was confirmed in the spinal cord and demonstrated in the dorsal root ganglion for both orexin-A and the orexin-1 receptor. The link with nociception was extended when orexin-A was shown to be analgesic when given i.v. but not s.c. in mouse and rat models of nociception and hyperalgesia. The efficacy of orexin-A was similar to that of morphine in the 50 degrees C hotplate test and the carrageenan-induced thermal hyperalgesia test. However, involvement of the opiate system in these effects was ruled out as they were blocked by the orexin-1 receptor antagonist SB-334867 but not naloxone. Orexin-1 receptor antagonists had no effect in acute nociceptive tests but under particular inflammatory conditions were pro-hyperalgesic, suggesting a tonic inhibitory orexin drive in these circumstances. These data demonstrate that the orexinergic system has a potential role in the modulation of nociceptive transmission.
GABA B receptors are G-protein-coupled receptors that mediate slow synaptic inhibition in the brain and spinal cord. These receptors are heterodimers assembled from GABA B1 and GABA B2 subunits, neither of which is capable of producing functional GABA B receptors on homomeric expression. GABA B1, although able to bind GABA, is retained within the endoplasmic reticulum (ER) when expressed alone. In contrast, GABA B2 is able to access the cell surface when expressed alone but does not couple efficiently to the appropriate effector systems or produce any detectable GABA-binding sites. In the present study, we have constructed chimeric and truncated GABA B1 and GABA B2 subunits to explore further GABA B receptor signaling and assembly. Removal of the entire C-terminal intracellular domain of GABA B1 results in plasma membrane expression without the production of a functional GABA B receptor. However, coexpression of this truncated GABA B1 subunit with either GABA B2 or a truncated GABA B2 subunit in which the C terminal has also been removed is capable of functional signaling via G-proteins. In contrast, transferring the entire C-terminal tail of GABA B1 to GABA B2 leads to the ER retention of the GABA B2 subunit when expressed alone. These results indicate that the C terminal of GABA B1 mediates the ER retention of this protein and that neither of the C-terminal tails of GABA B1 or GABA B2 is an absolute requirement for functional coupling of heteromeric receptors. Furthermore although GABA B1 is capable of producing GABA-binding sites, GABA B2 is of central importance in the functional coupling of heteromeric GABA B receptors to G-proteins and the subsequent activation of effector systems.
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