High throughput screening using the recombinant human TRPV1 receptor was used to identify a series of pyridinylpiperazine ureas (3) as TRPV1 vanilloid receptor ligands. Exploration of the structure-activity relationships by parallel synthesis identified the essential pharmacophoric elements for antagonism that permitted further optimization via targeted synthesis to provide a potent orally bioavailable and selective TRPV1 modulator 41 active in several in vivo models.

energy storage, membrane components, and signaling. Extracellular hydrolysis of dietary TG in circulating lipoproteins yields FFAs and sn -2 MG, which are then taken up by cells ( 1,2 ). MGs are also produced intracellularly from membrane phospholipids and the consecutive action of phospholipase C and diacylglycerol lipase, or from the hydrolysis of stored TG by adipose TG lipase (ATGL) and hormone sensitive lipase (HSL) ( 2-5 ). The ultimate fate of intracellular MGs is hydrolysis to FFAs and glycerol or reesterifi cation by acyltransferases into diacylglycerol and TG ( 6, 7 ).MG lipase (MGL) is considered the rate-determining enzyme in MG catabolism. MGL accounts for roughly 85% of MG hydrolysis in the brain, with the remainder being catalyzed by the enzymes ABHD6 and ABHD12 ( 8,9 ). MGL is expressed in many other tissues as well, including brain, liver, skeletal muscle, adipose, and intestine ( 10-13 ). Within cells, MGL localizes to both the cytosolic and membrane fractions and hydrolyzes sn -1 and sn -2 MGs of varying acyl chain lengths and degrees of unsaturation, with almost no activity toward other lipids, such as TG and lyso-phospholipids ( 10,(14)(15)(16)(17)(18).MGL is involved in energy balance through two important functions. Abbreviations: AA, arachidonic acid; AEA, arachidonoyl ethanolamide; 2-AG, 2-arachidonoyl glycerol; AUC, area under the curve; CB, cannabinoid; EC, endocannabinoid; HFD, high-fat diet; HOMA-IR, homeostatic model assessment of insulin resistance; iMGL, mice that overexpress monoacylglycerol lipase specifi cally in the intestinal mucosa; LFD, low-fat diet; MG, monoacylglycerol; MGL, monoacylglycerol lipase; OFTT, oral fat tolerance test; OGTT, oral glucose tolerance test; RER, respiratory exchange ratio .

ABSTRACT-Opioid analgesics are a mainstay in the treatment of acute and chronic pain of multiple origins, but their side effects, such as constipation, respiratory depression, and abuse liability, adversely affect patients. The recent demonstration of the upregulation and membrane targeting of the ␦-opioid receptor (DOR) following inflammation and the consequent enhanced therapeutic effect of ␦-opioid agonists have enlivened the search for ␦-opioid analgesic agents. JNJ-20788560 [9-(8-azabicyclo-[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylic acid diethylamide] had an affinity of 2.0 nM for DOR (rat brain cortex binding assay) and a naltrindole sensitive DOR potency of 5.6 nM (5Ј-O-(3-[ 35 S]thio)triphosphate assay). The compound had a potency of 7.6 mg/kg p.o. in a rat zymosan radiant heat test and of 13.5 mg/kg p.o. in a rat Complete Freund's adjuvant RH test but was virtually inactive in an uninflamed radiant heat test.In limited studies, tolerance was not observed to the antihyperalgesic or antinociceptive effects of the compound. Unlike ibuprofen, JNJ-20788560 did not produce gastrointestinal (GI) erosion. Although morphine reduced GI motility at all doses tested and reached nearly full effect at the highest dose, JNJ-20788560 did not retard transit at the lowest dose and reached only 11% reduction at the highest dose administered. Unlike morphine, JNJ-20788560 did not exhibit respiratory depression (blood gas analysis), and no withdrawal signs were precipitated by the administration of opioid ( or ␦) antagonists. Coupled with the previously published lack of self-administration behavior of the compound by alfentanil-trained primates, these findings strongly recommend ␦-opioid agonists such as JNJ-20788560 for the relief of inflammatory hyperalgesia.The -opioid receptor (MOR) is the core target of marketed opioid analgesics, but the side effect profile and abuse liability propensity of these compounds impels the search for better and safer analgesic agents. Although the ␦-opioid receptor (DOR) has long been known to mediate at least a modest level of antinociception (Heyman et al., 1986;Rodriguez et al., 1986), recent work on its regulation during inflammation has provided new impetus to its targeting for the relief of inflammatory pain. Under basal conditions, DOR is located predominantly intracellularly, whereas MOR is localized Article, publication date, and citation information can be found at

Recently, a splicing variant of cyclooxygenase (COX)-1, arising via the retention of its intron 1, was identified in canine. It was called COX-3 and was reported to be differentially sensitive to inhibition by various nonsteroidal anti-inflammatory drugs (NSAIDs) as well as acetaminophen (Chandrasekharan et al., 2002). However, the existence of an orthologous splicing variant in human tissues has been questioned due to a reading frame shift and premature termination. In this study, we first confirmed the existence of intron 1-retained COX-1 in certain human tissues at both the mRNA and protein levels. Molecular biology studies revealed that three distinct COX-1 splicing variants exist in human tissues. The most prevalent of these variants, called COX-1b 1 , arises via retention of the entire 94 base pair (bp) of intron 1, leading to a shift in the reading frame and termination at bp 249. However, the other two variant types, called COX-1b 2 and COX-1b 3 , retain entire intron 1, but they are missing a nucleotide in one of two different positions, thereby encoding predicted full-length and likely COX-active proteins. Functional studies revealed that the COX-1b 2 is able to catalyze the synthesis of prostaglandin F 2␣ from arachidonic acid with K m and V max values of 0.54 M and 3.07 pmol/mg/ min, respectively. However, no significant differential selectivity for inhibition by selected NSAIDs was observed. Accordingly, we conclude that intron 1-retained human COX-1 is not likely to be the therapeutic target of acetaminophen or a candidate of COX-3.The commonly used nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, and naproxen, are known for their effects to relieve pain and inflammation and to reduce fever. This therapeutic benefit derives primarily from the ability to inhibit the activities of certain cyclooxygenase (COX) enzymes that are critically involved in de novo prostaglandin biosynthesis (Vane, 1971). To date, two isoforms of the COX enzyme, COX-1 and COX-2, have been identified (DeWitt and Smith, 1988;Merlie et al., 1988;Hla and Neilson, 1992). These two isozymes have different expression patterns and distinct enzymatic properties. It has been suggested that COX-1, constitutively expressed in many tissues, is responsible for the physiological production of prostanoids, whereas COX-2, inducible under inflammatory conditions, is mainly responsible for the pathological production of prostanoids (O'Banion et al., 1992). Subsequent experiments determined that most of the clinically used COX inhibitors, such as ibuprofen and naproxen, were nonselective (i.e., they blocked both COX-1 and COX-2), albeit with varying potency ratios. Consequently, the major therapeutic limitation of the nonselective COX inhibitors has been their tendency to cause gastrointestinal lesions due to reductions in gut levels of homeostatic prostanoids via COX-1 inhibition. Accordingly, significant effort has been committed to the discovery and development of selective COX-2 inhibitors that would be expe...

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