The asymmetric addition of terminal alkynes to r-keto ester was carried out using a catalytic amount of (1S,2S)-3-(tert-butyldimethylsilyloxyl)-2-N,N-(dimethylamino)-1-(p-nitrophenyl)-propane-1-ol in the presence of Zn(OTf) 2 to give the corresponding tertiary propargylic alcohols in high yields with up to 94% ee. N-Methylephedrine and Zn(OSO 2 CHF 2 ) 2 were also examined in this reaction.

The transient receptor potential vanilloid 1 receptor (TRPV1) is expressed predominantly in a subset of primary afferent nociceptors. Due to its specific anatomical location and its pivotal role as a molecular integrator for noxious thermal and chemical stimuli, there is considerable interest to develop TRPV1 antagonists for the treatment of pain. Recently, N-(4-chlorobenzyl)- thiourea (IBTU) was synthesized, and it was found in vitro to be a high-affinity competitive antagonist of cytoplasmic, but not intracellular, TRPV1. In this study, we examined the in vivo antinociceptive activity of IBTU in several acute and inflammatory pain models in mice. Our emphasis was on nociceptive pathways that are likely mediated by TRPV1, including capsaicin-, noxious heat-, and proton (including inflammation)-induced nociception tests. Capsazepine was used as a positive control in these experiments. IBTU dose-dependently blocked the capsaicin-induced nociception, confirming its antagonism at TRPV1 in vivo. By itself, IBTU produced significant antinociception, because it significantly prolonged the tail-flick latency in a dose-dependent manner. IBTU also blocked both early and late phases of the formalin-induced flinching response as well as acetic acidinduced writhing behavior. Moreover, IBTU inhibited the complete Freund's adjuvant-induced persistent hyperalgesia. Taken together, these data demonstrate that IBTU acts as a TRPV1 antagonist in vivo, and they suggest that it may be of therapeutic use for the treatment of pain.The transient receptor potential vanilloid 1 receptor (TRPV1, formerly called VR1) is a nonselective cationic ion channel that is predominantly expressed in small-to-medium-diameter sensory neurons (Caterina et al., 1997;Hayes et al., 2000;McIntyre et al., 2001). These pain-sensing primary afferent neurons, also called nociceptors, are thought to release proinflammatory and pronociceptive mediators in the periphery and to transmit nociceptive information to the spinal cord (Szallasi and Blumberg, 1999). TRPV1 is activated by a variety of stimuli, including noxious heat (Ͼ43°C), protons (e.g., low pH environment caused by inflammation), and specific ligands such as capsaicin, the pungent ingredient of chili peppers (Caterina et al

A new inexpensive chiral amino alcohol-based ligand, (1S,2S)-2-N,N-dimethylamino-1-(p-nitrophenyl)-3- (t-butyldimethylsilyloxy)propane-1-ol, was developed for the asymmetric alkynylation of aliphatic and aromatic aldehydes, to prepare the corresponding propargylic alcohols in high yields with up to 99% ee.

No abstract

No abstract

No abstract

No abstract

We describe the synthesis and characterization of N-(4-chlorobenzyl) -NЈ-(4-hydroxy-3-iodo-5-methoxybenzyl)thiourea (IBTU), a novel antagonist of the vanilloid receptor 1 (TRPV1 or VR1). IBTU competitively inhibited 45 Ca 2ϩ uptake into CHO cells heterologously expressing rat TRPV1, whether induced by capsaicin or resiniferatoxin (K i ϭ 99 Ϯ 23 and 93 Ϯ 34 nM, respectively). IBTU was thus somewhat more potent (5-fold) than capsazepine. In contrast to its antagonism of vanilloid-induced calcium uptake, IBTU (30 M) inhibited [ 3 H]resiniferatoxin binding to TRPV1 by less than 10%. We hypothesize that these dramatically distinct potencies reflect different fractions of TRPV1 in this system: namely, a minor plasma membrane fraction controlling 45 Ca 2ϩ uptake, and the predominant intracellular fraction that dominates the [ 3 H]resiniferatoxin binding measurements. Intracellular Ca 2ϩ imaging supports this explanation.IBTU antagonized the elevation in intracellular Ca 2ϩ in response to 50 nM capsaicin with an IC 50 of 106 Ϯ 35 nM. Likewise, 600 nM IBTU was able to antagonize the elevation in intracellular Ca 2ϩ in response to 100 pM resiniferatoxin in the presence of normal (1.8 mM) extracellular Ca 2ϩ , where the increase in intracellular calcium reflects calcium influx. In contrast, in the absence of extracellular Ca 2ϩ , where in this system resiniferatoxin induces a modest increase in calcium from intracellular stores, IBTU was unable to block the response to resiniferatoxin, although the TRPV1 antagonist 5-iodoresiniferatoxin was able to do so. In summary, IBTU is a novel, potent TRPV1 antagonist with marked selectivity between subpopulations of TRPV1 and may permit the function of these distinct pools to be explored and potentially exploited.The vanilloid receptor TRPV1 is a polymodal integrator of noxious stimuli (Caterina et al., 1997), including low pH, heat, and ligands such as capsaicin, the pungent constituent in red pepper. Because of its function as a nociceptor, TRPV1 has attracted much attention as a novel, potential therapeutic target for the treatment of pain and other conditions involving C fiber sensory neurons (Kress and Zeilhofer, 1999;Caterina and Julius, 2001). Such applications include bladder hyperreflexia, detrusor instability, postmastectomy pain, mucositis, interstitial cystitis, pharyngitis, pancreatitis, enteritis, cellulitis, postherpetic neuralgia, peripheral neuropathy, arthritis, and bony fractures (Robbins, 2000).The characterization of novel natural products, such as resiniferatoxin, an ultrapotent TRPV1 agonist, and the emerging wealth of synthetic capsaicin analogs are driving a rapidly developing appreciation of the complexities of vanilloid pharmacology. Two general strategies for therapeutic intervention have received much attention. First, activation of TRPV1 by agonists is followed by desensitization/defunctionalization. As illustrated for resiniferatoxin or for olvanil, the acute response of pungency and the chronic response of desensitization/defunctionalization...