Search for lead structures to develop new allosteric modulators of muscarinic receptors

Various compounds are known to allosterically modulate the binding of ligands to muscarinic receptors. Most of these compounds have another predominant pharmacological action. Identification of the potent representatives should be useful for the development of allosteric modulators that are specific and highly active. For various reasons, a direct comparison of allosteric potencies on the basis of literature data is difficult. Therefore, a series of compounds was compared with regard to the allosteric delay of the dissociation of N-[3H]methylscopolamine from porcine heart M2 receptors under the following assay conditions: "Na,K,Pi buffer", 4 mM Na2HPO4, 1 mM KH2PO4, pH 7.4, 23 degrees C; "Mg,Tris,Cl,Pi buffer', 50 mM Tris-HCl, 3 mM MgHPO4,pH 7.3, 37 degrees C. Generally, the allosteric potency of the compounds was higher in the Na,K,Pi buffer, compared with the Mg,Tris,Cl,Pi buffer. However, the extent of the potency shift differed, ranging from approximately 2-fold for tacrine to approximately 100-fold for gallamine. The concentration retarding radioligand dissociation to half of the control rate (EC50) served as a measure of allosteric potency. Under both assay conditions, alcuronium was the most potent compound (EC50,Na,K,Pi = 4 nM and EC50,Mg,Tris,Cl,Pi = 55 nM), followed by alkane-bisammonium and bispyridinium compounds containing phthalimido moieties. Gallamine showed intermediate potency (EC50 values of 180 nM and 16,000 nM in Na,K,Pi buffer and Mg,Tris,Cl,Pi buffer, respectively). Obidoxime and hexamethonium, both known to antagonize allosteric actions, revealed submaximal efficacy and low potency (EC50,Na,K,Pi of approximately 100,000 nM). The relevance of these results, regarding the identification of lead structures for the development of new allosteric modulators, is discussed.     

Industrialization of LHC main quadrupole cold masses up to series production

Whereas the prototypes of the main quadrupoles had been pursued at CEA Saclay under contract with CERN, the contract to build all MQ magnets and the complete cold masses had been placed with ACCEL Instruments GmbH. After careful evaluation of design concepts and fabrication processes some revisions have been introduced to ease an industrial fabrication of the 400 MQ magnets and cold masses to be delivered to CERN. First batches of magnets were successfully cold tested. We report about the upgrading of the fabrication facility including the MQ specific layout of all machinery, the upgrading and qualifying of personnel resources and processes, the technical performance of the products and main activities and experiences on the way to series production.     

Fabrication of the pre-series wide aperture superconducting quadrupoles for the LHC insertions

Individually powered superconducting quadrupoles with a coil bore of 70 mm will be installed in the LHC insertions, in areas where increased geometrical acceptance and improved field quality are required. The quadrupoles feature a four-layer coil, designed on the basis of two graded 8.3 mm wide Rutherford-type NbTi cables. The magnets have a magnetic length of 3.4 m and a nominal gradient of 160 T/m at 4.5 K and 3610 A. A total of 26 quadrupoles are in production at ACCEL Instruments (Germany). In this report, we present the experience in fabrication of the pre-series magnets and the results of the initial qualification tests.