1 The reversible fatty acid amide hydrolase (FAAH) inhibitor OL135 reverses mechanical allodynia in the spinal nerve ligation (SNL) and mild thermal injury (MTI) models in the rat. The purpose of this study was to investigate the role of the cannabinoid and opioid systems in mediating this analgesic effect. À/À mice. 5 OL135 given i.p. resulted in a dose-responsive reversal of mechanical allodynia in both MTI and SNL models in the rat with an ED 50 between 6 and 9 mg kg À1 . The plasma concentration at the ED 50 in both models was 0.7 mM (240 ng ml À1 ). 6 In the rat SNL model, coadministration of the selective CB 2 receptor antagonist SR144528 (5 mg kg À1 i.p.), with 20 mg kg À1 OL135 blocked the OL135-induced reversal of mechanical allodynia, but the selective CB 1 antagonist SR141716A (5 mg kg À1 i.p.) was without effect. 7 In the rat MTI model neither SR141716A or SR144528 (both at 5 mg kg À1 i.p.), or a combination of both antagonists coadministered with OL135 (20 mg kg À1) blocked reversal of mechanical allodynia assessed 30 min after dosing. 8 In both the MTI model and SNL models in rats, naloxone (1 mg kg À1 , i.p. 30 min after OL135) reversed the analgesia (to 15% of control levels in the MTI model, to zero in the SNL) produced by OL135.

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to de®ne precisely the role of 5-HT 2B receptors in normal and disease processes have been hindered by the absence of selective antagonists. To address this de®ciency, we developed a series of naphthylpyrimidines as potentially useful 5-HT 2B receptor antagonists. 2 RS-127445 (2-amino-4-(4-¯uoronaphth-1-yl)-6-isopropylpyrimidine) was found to have nanomolar a nity for the 5-HT 2B receptor (pK i =9.5+0.1) and 1,000 fold selectivity for this receptor as compared to numerous other receptor and ion channel binding sites. 3 In cells expressing human recombinant 5-HT 2B receptors, RS-127445 potently antagonized 5-HTevoked formation of inositol phosphates (pK B =9.5+0.1) and 5-HT-evoked increases in intracellular calcium (pIC 50 =10.4+0.1). RS-127445 also blocked 5-HT-evoked contraction of rat isolated stomach fundus (pA 2 =9.5+1.1) and (+)a-methyl-5-HT-mediated relaxation of the rat jugular vein (pA 2 =9.9+0.3). RS-127445 had no detectable intrinsic activity in these assays. 4 In rats, the fraction of RS-127445 that was bioavailable via the oral or intraperitoneal routes was 14 and 60% respectively. Intraperitoneal administration of RS-127445 (5 mg kg 71 ) produced plasma concentrations predicted to fully saturate accessible 5-HT 2B receptors for at least 4 h. 5 In conclusion, RS-127445 is a selective, high a nity 5-HT 2B receptor antagonist suitable for use in vivo. The therapeutic potential of this molecule is being further evaluated.

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.