Organocatalyzed enantioselective fluorocyclizations.

Enantioenriched fluorinated heterocycles can be prepared through fluorocyclizations of prochiral indoles (see scheme; Ts=tosyl, Bn=benzyl, Boc=tert-butoxycarbonyl). More than twenty examples for this cascade fluorination-cyclization, which is catalyzed by cinchona alkaloids and employs N-fluorobenzenesulfonimide as the electrophilic fluorine source have been explored, and an unprecedented catalytic asymmetric difluorocyclization has also been identified.

5-HT in the enteric nervous system: gut function and neuropharmacology.

In recent times, the perception of functional gastrointestinal disorders such as irritable bowel syndrome (IBS) has shifted fundamentally. Such disorders are now thought of as serious diseases characterized by perturbations in the neuronal regulation of gastrointestinal function. The concept of visceral hypersensitivity, the characterization of neuronal networks in the 'brain-gut axis' and the identification of several novel 5-HT-mediated mechanisms have contributed to this shift. Here, we review how some of the more promising of these new mechanisms (e.g. those involving 5-HT transporters and the 5-HT(2B), 5-HT(7) and putative 5-HT(1p) receptors) might lead to a range of second-generation therapies that could revolutionize the treatment of functional gastrointestinal disorders, particularly IBS.

The role of adenosine A2A and A2B receptors in the regulation of TNF-alpha production by human monocytes.

Adenosine is an endogenous nucleoside that regulates many physiological processes through the activation of its four receptors: A(1), A(2A), A(2B) and A(3). Previous studies have identified the involvement of A(2) receptors in the inhibitory activity of adenosine analogues on tumor necrosis factor-alpha (TNF-alpha) production by lipopolysaccharide (LPS) activated monocytes, but the relative contributions of A(2A) versus A(2B) receptors have not been determined in human primary monocytes. Nor has the role of A(1) and A(3) been clearly identified in the system. The lack of such information impacts on the selection of adenosine receptor agonists for disease intervention. Using LPS-stimulated human primary monocytes, we found that the adenosine receptor agonist, 5'-N-ethylcarboxamidoadenosine (NECA) or the A(2A) receptor agonist, 4-[2-[[6-amino-9-(N-ethyl-b-d-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl]benzenepropanoic acid hydrochloride (CGS21680) produced a concentration-dependent inhibition of TNF-alpha production, with IC(50)s of 58.4nM (32.7-104.5nM, 95% confidence interval) and 49.2nM (22.7-105.9nM, 95% confidence interval), respectively. The selective A(2A) receptor blocker, 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylaminso]ethyl)phenol (ZM241385, 30nM), antagonized the effects of NECA and CGS21680 (pK(B) estimates were 8.7+/-0.1 and 8.9+/-0.1, respectively), while the selective A(2B) antagonist, N-(4-cyano-phenyl)-2-[4-(2,6-dioxo-1,3-dipropyl-2,3,4,5,6,7-hexahydro-1H-purin-8-yl)-phenoxy]-acetamide (MRS1754, 100nM), failed to antagonize the effects of either agonist. Furthermore, neither the A(1) receptor agonist, 2-chloro-N(6)-cyclopentyladenosine (CCPA) nor the A(3) receptor agonist, 1-[2-chloro-6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-1-deoxy-N-methyl-b-d-ribofuranuronamide (2-Cl-IB-MECA) showed significant inhibitory activity at concentrations that effectively bind to their respective receptors. We conclude that A(2A) receptor activation is predominantly responsible for the inhibitory effects of adenosine receptor agonists on TNF-alpha production from LPS-stimulated monocytes.

Quantitative mRNA expression profiling of ACE 2, a novel homologue of angiotensin converting enzyme.

ACE 2, a novel homologue of angiotensin converting enzyme, has recently been identified. This study used QRT-PCR to quantitatively map the transcriptional expression profile of ACE 2 (and the two isoforms of ACE) in 72 human tissues. While confirming that ACE 2 expression is high in renal and cardiovascular tissues, the novel observation has been made that ACE 2 shows comparably high levels of expression in the gastrointestinal system, in particular in ileum, duodenum, jejunum, caecum and colon. Therefore, in probing the functional significance of this novel peptidase, some consideration should be given to a role in gastrointestinal physiology and pathophysiology.

EP4 receptors mediate prostaglandin E2, tumour necrosis factor alpha and interleukin 1beta-induced ion secretion in human and mouse colon mucosa.

Prostaglandin E(2) (PGE(2)) is an inflammatory mediator implicated in several gastrointestinal pathologies that cause diarrhoea. The aim of this study was to establish the contributions of the four different EP receptors (EP(1-4)) to PGE(2)-induced anion secretion in human and mouse colon mucosa. Electrogenic anion secretion (short-circuit current; I(sc)) was measured across colonic mucosae or T84 monolayers placed in Ussing chambers in response to EP receptor agonists and antagonists. PGE(2) and PGE(1)-alcohol increased I(sc) in human colon mucosa, T84 epithelia and mouse colon mucosa, and these responses were inhibited by the EP(4) receptor antagonist, GW627368X alone. In addition, the EP(2) agonist, butaprost increased I(sc) in all three preparations and these responses were inhibited by the non-selective EP(1,2,3) receptor antagonist, AH6809 but not by GW627368X. Conversely, responses mediated by EP(1) and EP(3) receptors were not observed in human colon or T84 monolayers. However, in mouse colon mucosa the EP(3)-preferring agonist, sulprostone reduced I(sc), indicative of G(iα)-signalling. Taken together these results indicate that PGE(2)-induced ion secretion is mediated predominantly by G(s)-coupled EP(4) receptors and also by EP(2) receptors in human mucosa. Furthermore, tumour necrosis factor alpha (TNFα) and interleukin 1beta (IL1ß) increased I(sc) and these responses were also inhibited by the EP(4) receptor antagonist in human colon mucosa. This study establishes the EP receptor pharmacology present in human epithelial preparations, and suggests that EP(4) receptors may be a therapeutic target for the treatment of secretory diarrhoea where PGE(2) is implicated in the aetiology.