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781.
Although the dominant approach to drug development is the design of compounds selective for a given target, compounds targeting more than one biological process may have superior efficacy, or alternatively a better safety profile than standard selective compounds. Here, this possibility has been explored with respect to the endocannabinoid system and pain. Compounds inhibiting the enzyme fatty acid amide hydrolase (FAAH), by increasing local endocannabinoid tone, produce potentially useful effects in models of inflammatory and possibly neuropathic pain. Local increases in levels of the endocannabinoid anandamide potentiate the actions of cyclooxygenase inhibitors, raising the possibility that compounds inhibiting both FAAH and cyclooxygenase can be as effective as non-steroidal anti-inflammatory drugs but with a reduced cyclooxygenase inhibitory ‘load’. An ibuprofen analogue active in models of visceral pain and with FAAH and cyclooxygenase inhibitory properties has been identified. Another approach, built in to the experimental analgesic compound N-arachidonoylserotonin, is the combination of FAAH inhibitory and transient receptor potential vanilloid type 1 antagonist properties. Although finding the right balance of actions upon the two targets is a key to success, it is hoped that dual-action compounds of the types illustrated in this review will prove to be useful analgesic drugs. 相似文献
782.
Solberg BC Dirksen CD Nieman FH van Merode G Poeze M Ramsay G 《Critical care (London, England)》2008,12(3):R68
Introduction
The high cost of critical care resources has resulted in strategies to reduce the costs of ruling out low-risk patients by developing intermediate care units (IMCs). The aim of this study was to compare changes in total hospital costs for intensive care patients before and after the introduction of an IMC at the University Hospital Maastricht. 相似文献783.
CJ. Zhao C. Noack M. Brackmann T. Gloveli A. Maelicke U. Heinemann R. Anand K.H. Braunewell 《Molecular and cellular neurosciences》2009,40(2):280-292
The neuronal Ca2+-sensor protein VILIP-1, known to affect clathrin-dependent receptor trafficking, has been shown to interact with the cytoplasmic loop of the α4-subunit of the α4β2 nicotinic acetylcholine receptor (nAChR), which is the most abundant nAChR subtype with high-affinity for nicotine in the brain. The α4β2 nAChR is crucial for nicotine addiction and the beneficial effects of nicotine on cognition. Its dysfunction has been implicated in frontal lobe epilepsy, Alzheimer's disease and schizophrenia. Here we report that overexpression of VILIP-1 enhances ACh responsiveness, whereas siRNA against VILIP-1 reduces α4β2 nAChR currents of hippocampal neurons. The underlying molecular mechanism likely involves enhanced constitutive exocytosis of α4β2 nAChRs mediated by VILIP-1. The two interaction partners co-localize in a Ca2+-dependent manner with syntaxin-6, a Golgi-SNARE protein involved in trans-Golgi membrane trafficking. Thus, we speculate that regulation of VILIP-1-expression might modulate surface expression of ligand-gated ion channels, such as the α4β2 nAChRs, possibly comprising a novel form of physiological up-regulation of ligand-gated ion channels. 相似文献
784.
Alanine substitution mutagenesis has been used to investigate residues that make up the roof and floor of the muscarinic binding pocket and regulate ligand access. We mutated the amino acids in the second extracellular loop of the M1 muscarinic acetylcholine receptor that are homologous to the cis-retinal contact residues in rhodopsin, the disulfide-bonded Cys178 and Cys98 that anchor the loop to transmembrane helix 3, the adjoining acidic residue Asp99, and the conserved aromatic residues Phe197 and Trp378 in the transmembrane domain. The effects on ligand binding, kinetics, and receptor function suggest that the second extracellular loop does not provide primary contacts for orthosteric ligands, including acetylcholine, but that it does contribute to microdomains that are important for the conformational changes that accompany receptor activation. Kinetic studies suggest that the disulfide bond between Cys98 and Cys178 may contribute to structures that regulate the access of positively charged ligands such as N-methyl scopolamine to the binding pocket. Asp99 may act as a gatekeeper residue to this channel. In contrast, the bulkier lipophilic ligand 3-quinuclidinyl benzilate may require breathing motions of the receptor to access the binding site. Trp378 is a key residue for receptor activation as well as binding, whereas Phe197 represents the floor of the N-methyl scopolamine binding pocket but does not interact with acetylcholine or 3-quinuclidinyl benzilate. Differences between the binding modes of N-methyl scopolamine, 3-quinuclidinyl benzilate, and acetylcholine have been modeled. Although the head groups of these ligands occupy overlapping volumes within the binding site, their side chains may follow significantly different directions. 相似文献