Nonspecific structure-activity relationships

For both nonspecific and structure-based approaches, physicochemical solvation parameters may be used directly, or they may be embedded in quantitative structure-activity relationships.3 This chapter starts with a review of the thermodynamic equations that may be used for a quantitative description of the free energy of solutes in fluid media. Then it provides an... 

Ikemoto, Y., Motoba, K., Suzuki, T., and Uchida, M. Quantitative structure-activity relationships of nonspecific and specific toxicants in several organism species, Environ. Toxicol Chem., ll(7) 931-939,1992. 

Key words Alkaline phosphatase. Intestinal alkaline phosphatase. Tissue-nonspecific alkaline phosphatase, Placental alkaline phosphatase. High throughput assay, Chemilmninescence, CDP-star, Inhibition, Activation, Structure-activity relationship... 

The nonspecific membrane actions of local anesthetics can be easily ruled out, because most clinically useful agents, in contrast to general anesthetics, possess a defined set of structure-activity relationships. As mentioned earlier, local anesthetic agents block nerve conductance and produce anesthesia as a result of their selective actions on membrane-bound sodium channels. It should be pointed out that at much higher drug concentrations, local anesthetics also bind and block potassium channels. 

No information is available at present on the effects of the many other secondary bile acids present in feces in small concentrations on water and electrolyte movement in the colon. In addition, no information is available on the role of bile acids in constipation, irritable bowel syndrome, nonspecific diarrhea, antibiotic diarrhea, or the diarrhea of the germ-free animal. Of interest is the response of the diarrhea of the germ-free animal to an anion exchange resin similar to cholestyramine (112). Studies are needed to define the structure-activity relationships for bile acids and the induction of water and sodium secretion by the colon. In addition, information is needed on the composition, concentration, and physical state of bile acids in colonic contents and feces in health and disease. 

Nonspecific Inhibition - The use of log P in the correlation of the structure-activity relationship in a wide variety of narcotics has shown a linear relation between log 1/C and log P for 16 different systems with slopes near 1. The similar equations point to a common mechanism of action, possibly the inhibition of electron transport in oxidative metabolism. The use of log P for relating the effect of different sets of congeners acting on different biological systems Is Indicated in eq 9 and 10. 

NMR and kinetic studies have been conducted with the hope of providing more details about the position and conformation of the polypeptide substrate in cAMP-dependent protein kinase. These have served to narrow down the possible spatial relationships between enzyme bound ATP and the phosphorylated serine. Thus, a picture of the active site that is consistent with the available data can be drawn (12,13,66,67). Although these studies have been largely successful at eliminating some classes of secondary polypeptide structure such as oi-hellces, 6-sheets or an obligatory 6-turn conformation 66), the precise conformation of the substrate is still not known. The data are consistent with a preference for certain 6-turn structures directly Involving the phosphorylated serine residue. However, they are also consistent with a preference or requirement for either a coil structure or some nonspecific type of secondary structure. Models of the ternary active-site complexes based on both the coil and the, turn conformations of one alternate peptide substrate have" been constructed (12). These two models are consistent with the available kinetic and NMR data. 

Fig. 4 In situ zymography and immunohistochemistry of MMPs Relationship with BBB disruption induced by HIV-1 gpl 20. (a) Injection of gpl 20 into the rat CP induced upregulation of matrix metalloproteinases (MMPs). Frozen cryostat sections of CP injected with 500 ng gpl 20 and stained by in situ zymography. Left column The fluorescent product was observed in blood vessel-like structures and in cells. Middle column-. Positive control. In situ zymography detects intense fluorescence in the hippocampus. Right coiumrr. No gelatinolytic activity was seen In the contralateral unInjected side or in CPs injected with saline (not shown), neither when a section of the test brain was incubated with 1,10-phenanthroline, a nonspecific inhibitor of MMP activity, (b) There was a colocalization between In situ zymography and RECA-1. (c) Colocalization between MMP-2 and the endothelial cell marker RECA-1 In CPs Injected with gpl 20. MMP abnormalities were associated with EB leakage (not shown in this panel) (modified from [25,48,105])...

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