Alcohol receptor studies

Apart from these two Vertex compounds, only one other caspase inhibitor, BDN-6556, has been used in clinical trials. This compound belongs to the class of oxamyl dipeptides and was originally developed by Idun Pharmaceuticals (taken over by Pfizer). It is the only pan-caspase inhibitor that has been evaluated in humans. BDN-6556 displays inhibitory activity against all tested human caspases. It is also an irreversible, caspase-specific inhibitor that does not inhibit other major classes of proteases, or other enzymes or receptors. The therapeutic potential of BDN-6556 was first evaluated in several animal models of liver disease because numerous publications suggested that apoptosis contributes substantially to the development of some hepatic diseases, such as alcoholic hepatitis, hepatitis B and C (HBV, HCV), non-alcoholic steato-hepatitis (NASH), and ischemia/reperfusion injury associated with liver transplant. Accordingly, BDN-6556 was tested in a phase I study. The drug was safe and... 

These findings were unexpected because previous studies had demonstrated that the y2 subunit is required for potentiation of GABAa receptor function by low concentrations of ethanol [2]. The y2 subunit gene is located within a definitely mapped quantitative trait locus (QTL) for acute alcohol withdrawal on mouse chromosome 11 [1]. Allelic variation was genetically... 

Findings from animal studies suggest that neuropeptide Y (NPY) may be associated with ethanol consumption. NPY-deficient mice have increased alcohol consumption (Thiele et al. 1998), an effect that is mediated by the Y1 and Y2 receptors (Pandey et al. 2003 Thiele et al. 2000, 2002). It has been suggested that NPY Y1 agonists and Y2 antagonists may have promise in the treatment of alcoholism (Cowen et al. 2004). 

Farde L, Pauli S, Litton JE, et al PET-determination of benzodiazepine receptor binding in studies on alcoholism. EXS 71 143—153, 1994... 

In 1868 two Scottish scientists, Crum Brown and Fraser [4] recognized that a relation exists between the physiological action of a substance and its chemical composition and constitution. That recognition was in effect the birth of the science that has come to be known as quantitative structure-activity relationship (QSAR) studies a QSAR is a mathematical equation that relates a biological or other property to structural and/or physicochemical properties of a series of (usually) related compounds. Shortly afterwards, Richardson [5] showed that the narcotic effect of primary aliphatic alcohols varied with their molecular weight, and in 1893 Richet [6] observed that the toxicities of a variety of simple polar chemicals such as alcohols, ethers, and ketones were inversely correlated with their aqueous solubilities. Probably the best known of the very early work in the field was that of Overton [7] and Meyer [8], who found that the narcotic effect of simple chemicals increased with their oil-water partition coefficient and postulated that this reflected the partitioning of a chemical between the aqueous exobiophase and a lipophilic receptor. This, as it turned out, was most prescient, for about 70% of published QSARs contain a term relating to partition coefficient [9]. 

The use of structurally rigid DKPs as bioactive models for opioid receptor antagonists has been proposed. These compounds are used in the elucidation of the binding requirements and will lead to the design of highly selective molecules with potential clinical application for diseases of the opioid system. These include the treatment of autism, alcohol dependency, and modulation of immunity Further studies by Baures has... 

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