http://www.back-in-business-physiotherapy.com/images/files/DescendingControl.pdf

Descending control of pain.

Years of cumulative research can result in the development of a clinically useful drug, providing either a cure for a particular disease or symptomatic relief from a physiological disorder. A lead compound with a desired pharmacological activity may have associated with it undesirable side effects, characteristics that limit its bioavailability, or structural features which adversely influence its metabolism and excretion from the body. Bioisosterism represents one approach used by the medicinal chemist for the rational modification of lead compounds into safer and more clinically effective agents. The concept of bioisosterism is often considered to be qualitative and intuitive.1 The prevalence of the use of bioisosteric replacements in drug design need not be emphasized. This topic has been reviewed in previous years.2-5 The objective of this review is to provide an overview of bioisosteres that incorporates sufficient detail to enable the reader to understand the concepts being delineated. While a few popular examples of the successful use of bioisosteres have been included, the George Patani graduated with a B.Pharm. in 1992 from the College of Pharmaceutical Sciences, Mangalore University at Manipal, India. In 1996, he received his M.S. in Pharmaceutical Science at Rutgers University under the direction of Professor Edmond J. LaVoie. He is presently pursuing graduate studies in pharmaceutics. His current research interests are focused on drug design and controlled drug delivery.

https://www.mch.estranky.sk/file/228/1996chemrev96-3147-76_bioisosterism.pdf

Bioisosterism: A Rational Approach in Drug Design.

Medicinal plants: Traditions of yesterday and drugs of tomorrow

We have provided a historical perspective on a body of steroid receptor research dealing with the structure and physiological significance of the untransformed 9S receptor that has often confused both novice and expert investigators. The frequent controversies and equivocations of earlier studies were due to the fact that the native, hormone-free state of these receptors is a large multiprotein complex that resisted description for many years because of its unstable and dynamic nature. The untransformed 9S state of the steroid and dioxin receptors has provided a unique system for studying the function of the ubiquitous, abundant, and conserved heat shock protein, hsp90. The hormonal control of receptor association with hsp90 provided a method of manipulating the receptor heterocomplex in a manner that was physiologically meaningful. For several steroid receptors, binding to hsp90 was required for the receptor to be in a native hormone-binding state, and for all of the receptors, hormone binding promoted dissociation of the receptor from hsp90 and conversion of the receptor to the DNA-binding state. Although the complexes between tyrosine kinases and hsp90 were discovered earlier, the hormonal regulation or steroid receptor association with hsp90 permitted much more rapid and facile study of hsp90 function. The observations that hsp90 binds to the receptors through their HBDs and that these domains can be fused to structurally different proteins bringing their function under hormonal control provided a powerful linkage between the hormonal regulation of receptor binding to hsp90 and the initial step in steroid hormone action. Because the 9S receptor hsp90 heterocomplexes could be physically stabilized by molybdate, their protein composition could be readily studied, and it became clear that these complexes are multiprotein structures containing a number of unique proteins, such as FKBP51, FKBP52, CyP-40, and p23, that were discovered because of their presence in these structures. Further analysis showed that hsp90 itself exists in a variety of native multiprotein heterocomplexes independent of steroid receptors and other 'substrate' proteins. Cell-free systems can now be used to study the formation of receptor heterocomplexes. As we outlined in the scheme of Fig. 1, the multicomponent receptor-hsp90 heterocomplex assembly system is being reconstituted, and the importance of individual proteins, such as hsp70, p60, and p23, in the assembly process is becoming recognized. It should be noted that our understanding of the mechanism and purpose of steroid receptor heterocomplex assembly is still at an early stage. We can now speculate on the roles of receptor-associated proteins in receptor action, both as individuals and as a group, but their actual functions are still vague or unknown. We can make realistic models about the chaperoning and trafficking of steroid receptors, but we don't yet know how these processes occur, we don't know where chaperoning occurs in the cell (e.g. Is it limited to the cytoplasm? Is it a diffuse process or does chaperoning occur in association with structural elements?), and, with the exception of the requirement for hormone binding, we don't know the extent to which the hsp90-based chaperone system impacts on steroid hormone action. It is not yet clear how far the discovery of this hsp90 heterocomplex assembly system will be extended to the development of a general understanding of protein processing in the cell. Because this assembly system is apparently present in all eukaryotic cells, it probably performs an essential function for many proteins. The bacterial homolog of hsp90 is not an essential protein, but hsp90 is essential in eukaryotes, and recent studies indicate that the development of the cell nucleus from prokaryotic progenitors was accompanied by the duplication of genes for hsp90 and hsp70 (698). (ABSTRACT TRUNCATED)

/pdf/steroid-receptor-interactions-with-heat-shock-protein-and-1iq19twpoc.pdf

Steroid receptor interactions with heat shock protein and immunophilin chaperones.

Medicinal plants of India with anti-diabetic potential.

Alloxan induced animal model was used to evaluate the potential antidiabetic effect of A. marmelose leaf extract. The diabetic animals were given insulin injection and another group A. marmelose leaf extract orally. It maintained the weight of the animals near to the control rats but a significant decrease in weight was noted in diabetic animals without any treatment. The blood glucose level in treated animals were near to that of control ones. Also a significantly increased glucose tolerance was observed in animals orally given the leaf extract prior to the experiment. A significant decrease in liver glycogen (1.24 +/- .07 g/100 g of wet tissue) was observed in diabetic rats which was brought to almost the normal level (1.84 +/- .14 g/100 g) with leaf extract treatment. Blood urea and serum cholesterol increased (62.66 +/- 3.50 and 192.67 +/- 13.64 mg/dl) significantly in alloxan diabetic rats. The leaf extract treatment decreased the blood urea and serum cholesterol (37.83 +/- 3.97 and 99.20 +/- 8.43 mg/dl) to that of control ones. A similar effect was seen with insulin treatment. The results indicate that the active principle in A. marmelose leaf extract has similar hypoglycaemic activity to insulin treatment.

Effect of leaf extract of Aegle marmelose in diabetic rats

Induction of DNA synthesis in primary cultures of rat hepatocytes by serotonin: Possible involvement of serotonin S2 receptor

Pyridoxal phosphate is the coenzyme of various decarboxylases involved in the formation of monoamine neurotransmitters such as gamma-aminobutyric acid, serotonin, dopamine, and norepinephrine. Adult male Sprague-Dawley rats placed on a pyridoxine-deficient diet for 8 weeks showed significant hypertension compared with pyridoxine-supplemented controls. Hypothalamic contents of pyridoxal phosphate, gamma-aminobutyric acid, and serotonin in the pyridoxine-deficient rats were significantly lower than those in pyridoxine-supplemented controls. Hypertension was associated with sympathetic stimulation. Treatment of pyridoxine-deficient rats with a single dose of pyridoxine (10 mg/kg body weight) reversed the blood pressure to normal levels within 24 hours, with concomitant restorations of hypothalamic serotonin and gamma-aminobutyric acid as well as the return of plasma norepinephrine and epinephrine to normal levels. Also, pyridoxine treatment reversed the hypothalamic hypothyroidism observed in pyridoxine-deficient rats. These results indicate an association between pyridoxine deficiency and sympathetic stimulation leading to hypertension.

Sympathetic stimulation and hypertension in the pyridoxine-deficient adult rat.

The functional basis of diabetes-mellitus to a certain extent, can be elucidated by studying diabetes-induced changes in metabolic enzymes. Malate dehydrogenase (MDH), is an enzyme directly involved in glucose metabolism. The kinetic parameters of MDH and its purified cytosolic isozyme, S-MDH, have been studied in the liver of streptozotocin-diabetic rats; also the potential of the leaf extract of A. marmelose as an anti-diabetic agent was investigated. The Km of the liver enzyme increased significantly, in both crude and purified preparations in the diabetic state when compared to the respective controls. Insulin as well as leaf-extract treatment of the diabetic rats brought about a reversal of Km values to near normal. Vmax of purified S-MDH was significantly higher in the diabetic state when compared to the control. Insulin and leaf extract treatment did not reverse this change. Since MDH is an important enzyme in glucose metabolism, the variation in its quantitative and qualitative nature may contribute to the pathological status of diabetes. The fact that leaf extract of A. marmelose was found to be as effective as insulin in restoration of blood glucose and body weight to normal levels, the use of A. marmelose as potential hypoglycemic agent is suggested.

Kinetic studies of purified malate dehydrogenase in liver of streptozotocin-diabetic rats and the effect of leaf extract of Aegle marmelose (L.) Correa ex Roxb.

C.S. Paulose

Papers

Effect of leaf extract of Aegle marmelose in diabetic rats

Induction of DNA synthesis in primary cultures of rat hepatocytes by serotonin: Possible involvement of serotonin S2 receptor

Sympathetic stimulation and hypertension in the pyridoxine-deficient adult rat.

Kinetic studies of purified malate dehydrogenase in liver of streptozotocin-diabetic rats and the effect of leaf extract of Aegle marmelose (L.) Correa ex Roxb.

Neurobiology of pyridoxine