Glucocorticoids structure

The optimum glucocorticoid structure shows a la, 2P-half-chair conformation for ring A, with ring D as a 13-envelope (C-13 is bent up) or a half-chair. Halogenation is most effective in positions 6, 7, 9, and 12. The compounds bind on their p face by hydrophobic binding forces. 

The individual domains of the two receptors both have structures similar to that of the glucocorticoid receptor, and they bind to DNA in a similar way, with their recognition helices in the major groove. The dimer contacts are, however, totally different. In the glucocorticoid receptor, which binds to a palindromic DNA sequence like the 434 repressor described in Chapter 8, the domains interact symmetrically in a head-to-head fashion equivalent... 

Hard, T., et al. Solution structure of the glucocorticoid receptor DNA-binding domain. Science 249 157-160, 1990. 

Hollenberg SM, Weinberger C, Ong ES et al (1985) Primary structure and expression of a functional human glucocorticoid receptor cDNA. Nature 318 635-641... 

This section of the chapter discusses the hormones produced by the adrenal cortex or the adrenocortical hormones, which are the glucocorticoids and mineralocorticoids. These hormones are essential to life and influence many organs and structures of the body. The glucocorticoids and mineralocorticoids are collectively called corticosteroids. 

Yates CR, Chang C, Kearbey JD, Yasuda K, Schuetz EG, Miller DD, et al. Structural determinants of P-glycoprotein-mediated transport of glucocorticoids. Pharm Res 2003 20 1794-803. 

Recently, Tse et al. [73] and Orlowski et al. [74] have cloned a third isoform of Na /H exchanger (named NHE-3). The inferred 832-amino acid sequence of rabbit NHE-3 is 41% identical with NHE-1, 44% identical with NHE-2, and has a similar secondary structure. In contrast to NHE-1 and NHE-2, NHE-3 is only expressed in epithelia in intestine and kidney. Moreover, administration of glucocorticoids, which stimulates transport activity of the apical Na /H" exchanger in rabbit intestine, increased levels of NHE-3 transcripts but did not affect NHE-1 or NHE-2 [75]. Taken together, these results suggest that NHE-3 may encode a resistant-type Na /H exchanger of epithelia. A fourth Na /H exchanger isoform (NHE-4) is preferentially expressed in stomach [74]. 

Arriza, J. L., Weinberger, C., Cerelli, G. et al. Cloning of the human mineralocorticoid receptor complementary DNA Structural and functional kinship with the glucocorticoid receptor. Science 237 268-275,1987. 

The Beato group has studied in depth the influence of the nucleosome structure in response to glucocorticoids (Beato 1989). Nucleosomes are formed by segments of 120 nucleotides of the double helix of DNA that make two twists around an octamer of histone. There are 200 nucleotides between two consecutive nucleosomes, so that a gene normally has tens of nucleosomes. 

Encio IJ, Detera-Wadleigh SD. (1991) The genomic structure of the human glucocorticoid receptor. J Biol Chem. 266, 7182-7188. 

Gehring U. (1993) The structure of glucocorticoid iecep.ots. J Steroid Biochem Mol Biol. 45, 183-190. 

Glucocorticoid receptors are present in a high density in the amygdala and neuroimaging studies have shown that the amygdala is the only structure in which the regional blood flow and glucose metabolism consistently correlate positively with the severity of depression. This... 

The introduction of a 9a-fluoro substituent increases anti-inflammatory activity, but it increases mineralocor-ticoid activity even more (300x). Fludrocortisone acetate is of little value as an anti-inflammatory, but it is employed as a mineralocorticoid. On the other hand, additional modifications may be employed. Introduction of a 1,2-double bond increases glucocorticoid activity over mineralocorticoid activity, and a 16-methyl group reduces mineralocorticoid activity without affecting glucocorticoid activity. A combination of these three structural modifications gives valuable anti-inflammatory drugs, e.g. betamethasone, with hardly any mineralocorticoid activity. ... 

---