Structural determinants of opioid and NOP receptor activity in derivatives of buprenorphine

The unique pharmacological profile of buprenorphine has led to its considerable success as an analgesic and as a treatment agent for drug abuse. Activation of nociceptin/orphanin FQ peptide (NOP) receptors has been postulated to account for certain aspects of buprenorphine’s behavioural profile. In order to investigate the role of NOP activation further, a series of buprenorphine analogues has been synthesised with the aim of increasing affinity for the NOP receptor. Binding and functional assay data on these new compounds indicate that the area around C20 in the orvinols is key to NOP receptor activity, with several compounds displaying higher affinity than buprenorphine. One compound, 1b, was found to be a mu opioid receptor partial agonist of comparable efficacy to buprenorphine, but with higher efficacy at NOP receptors

Search for the glueball candidates f0(1500) and fJ(1710) in gamma gamma collisions

Data taken with the ALEPH detector at LEP1 have been used to search for gamma gamma production of the glueball candidates f0(1500) and fJ(1710) via their decay to pi+pi-. No signal is observed and upper limits to the product of gamma gamma width and pi+pi- branching ratio of the f0(1500) and the fJ(1710) have been measured to be Gamma_(gamma gamma -> f0(1500)). BR(f0(1500)->pi+pi-) < 0.31 keV and Gamma_(gamma gamma -> fJ(1710)). BR(fJ(1710)->pi+pi-) < 0.55 keV at 95% confidence level.Comment: 10 pages, 3 figure

Search for supersymmetry with a dominant R-parity violating LQDbar couplings in e+e- collisions at centre-of-mass energies of 130GeV to 172 GeV

A search for pair-production of supersymmetric particles under the assumption that R-parity is violated via a dominant LQDbar coupling has been performed using the data collected by ALEPH at centre-of-mass energies of 130-172 GeV. The observed candidate events in the data are in agreement with the Standard Model expectation. This result is translated into lower limits on the masses of charginos, neutralinos, sleptons, sneutrinos and squarks. For instance, for m_0=500 GeV/c^2 and tan(beta)=sqrt(2) charginos with masses smaller than 81 GeV/c^2 and neutralinos with masses smaller than 29 GeV/c^2 are excluded at the 95% confidence level for any generation structure of the LQDbar coupling.Comment: 32 pages, 30 figure

“Essential—Passion for Music”: Affirming, Critiquing, and Practising Passionate Work in Creative Industries

This chapter considers “passion” as an enthusiastic orientation to work within creative worlds: work motivated by intense attachments to the products of work and their conditions of production. Drawing on Luc Boltanski’s pragmatic sociology of critique and justification, the chapter argues that the passionate lens most usefully trains our sights on normative questions: not what or how—but why such work is undertaken. Embedded in research on cultural and creative industries, the contemporary recorded music sector is presented as a “passionate” industry in transformation. Interviews with workers, who both criticize and defend their industry, act as a springboard to explore three possible interpretive approaches: affirmative, critical, and pragmatic. Theoretical flexibility is needed to keep “passion” open to future inquiry—particularly regarding inequalities in creative work

C4b Binding Protein Binds to CD154 Preventing CD40 Mediated Cholangiocyte Apoptosis: A Novel Link between Complement and Epithelial Cell Survival

Activation of CD40 on hepatocytes and cholangiocytes is critical for amplifying Fas-mediated apoptosis in the human liver. C4b-Binding Protein (C4BP) has been reported to act as a potential surrogate ligand for CD40, suggesting that it could be involved in modulating liver epithelial cell survival. Using surface plasmon resonance (BiaCore) analysis supported by gel filtration we have shown that C4BP does not bind CD40, but it forms stable high molecular weight complexes with soluble CD40 ligand (sCD154). These C4BP/sCD154 complexes bound efficiently to immobilised CD40, but when applied to cholangiocytes they failed to induce apoptosis or proliferation or to activate NFkB, AP-1 or STAT 3, which are activated by sCD154 alone. Thus C4BP can modulate CD40/sCD154 interactions by presenting a high molecular weight multimeric sCD154/C4BP complex that suppresses critical intracellular signalling pathways, permitting cell survival without inducing proliferation. Immunohistochemistry demonstrated co-localisation and enhanced expression of C4BP and CD40 in human liver cancers. These findings suggest a novel pathway whereby components of the complement system and TNF ligands and receptors might be involved in modulating epithelial cell survival in chronic inflammation and malignant disease

The new psychoactive substances 5-(2-aminopropyl)indole (5-IT) and 6-(2-aminopropyl)indole (6-IT) interact with monoamine transporters in brain tissue

In recent years, use of psychoactive synthetic stimulants has grown rapidly. 5-(2-Aminopropyl)indole (5-IT) is a synthetic drug associated with a number of fatalities, that appears to be one of the newest 3,4-methylenedioxymethamphetamine (MDMA) replacements. Here, the monoamine-releasing properties of 5-IT, its structural isomer 6-(2-aminopropyl)indole (6-IT), and MDMA were compared using in vitro release assays at transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT) in rat brain synaptosomes. In vivo pharmacology was assessed by locomotor activity and a functional observational battery (FOB) in mice. 5-IT and 6-IT were potent substrates at DAT, NET, and SERT. In contrast with the non-selective releasing properties of MDMA, 5-IT displayed greater potency for release at DAT over SERT, while 6-IT displayed greater potency for release at SERT over DAT. 5-IT produced locomotor stimulation and typical stimulant effects in the FOB similar to those produced by MDMA. Conversely, 6-IT increased behaviors associated with 5-HT toxicity. 5-IT likely has high abuse potential, which may be somewhat diminished by its slow onset of in vivo effects, whereas 6-IT may have low abuse liability, but enhanced risk for adverse effects. Results indicate that subtle differences in the chemical structure of transporter ligands can have profound effects on biological activity. The potent monoamine-releasing actions of 5-IT, coupled with its known inhibition of MAO A, could underlie its dangerous effects when administered alone, and in combination with other monoaminergic drugs or medications. Consequently, 5-IT and related compounds may pose substantial risk for abuse and serious adverse effects in human users