Hormone Receptor Agonists

4-Nonylphenol (environmental degradation product of some commercially-used surfactants) 

Retinoic Acid Receptor. Most of the biological effects of retinoids are mediated through the retinoic acid receptor (RAR) and the retinoid X receptor (RXR). Both all-/ran.s-retinoic acid and 9-d.v-rctinoic acid serve as agonists of RAR, while only 9-d.v-rctinoic acid functions as an agonist of RXR. The functional RAR exists as a heterodimer with RXR, while functional RXR exists as a homodimer. Methoprene is a juvenile hormone III analogue that mimics the activity of this insect hormone. 

Note Estrogenic potency of the compounds was measured using a recombinant yeast cell bioassay. 

Exposure of juvenile insects to methoprene results in various abnormalities associated with development and ultimately death. The environmental degradation product of methoprene, methoprenic acid was found to serve as an RXR agonist and specifically activate genes responsive to RXR homodimers. In addition exposure of frog larvae to methoprenic acid caused developmental deformities consistent with those that have been observed in recent years in wild populations and consistent with those caused by exposure to retinoic acid under laboratory conditions. These observations indicate that methoprenic acid functions as an RXR agonist, and that this activity could contribute to the occurrence of amphibians deformities documented in the environment. 

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Hormone receptors have some obvious and important pharmacologic distinctions. Drugs that can bind to and activate specific hormonal receptors (agonists) will mimic the effects of the endogenous compounds. Drugs that block the receptors (antagonists) will attenuate any unwanted hormonal effects. In fact,... 

There are several pro-angiogenic factors that promote angiogenesis (Table 2). Those include growth factors, hormone receptor agonists, pro-coagulants, extracellular matrix proteins, or glycosaminoglycans (GAGs). 

Table 11.2 Cytosolic non-steroid hormone receptor agonists and antagonists...

I. Nongenomic Thyroid Disorders T3 Thyroid Hormone Receptor Agonists... 

Levothyroxine 21 Thyroid hormone receptor (agonist) Specific form of thyroid hormones, namely T4, which has 4 iodines Endogenous hormone family (thyroid hormones T4, T3, where T3 has 3 iodines) h Hypothyroidism Overextensison of thyroid hormone activity... 

Boyer SH, Jiang H, Jacintho JD, Reddy MV, Li H, Li W, Godwin JL, Schulz WG, Cable EE, Hou J et al (2008) Synthesis and biological evaluation of a series of liver-selective phosphonic acid thyroid hormone receptor agonists and their prodrugs. J Med Chem 51 7075-7093... 

Boyer et al. synthesized and biologically evaluated a series of liver-selective phosphonic acids (PA) thyroid hormone receptor agonists (249) and their prodrugs to exploit the poor distribution of PA-based drugs to extrahepatic tissues and thereby to improve the therapeutic index. 

The term endocrine disrupter (ED) has tended to be used for those chemicals which act specifically at the level of the hormone receptor present in the target cells of various organs. Such chemicals may either mimic the action of the natural hormone (agonistic activity) or are sufficiently similar in molecular shape to the naturally produced hormone to interfere with the interaction between the hormone and receptor, thus blocking or impeding the activation of the receptor (antagonsitic activity). Such effects may occur at very low concentrations (as with the endogenous hormone), compared with the concentrations normally required to elicit the more traditional toxic effects attributed to chemicals. Recently,... 

Stimulation and inhibition of the enzyme by the GPCR-G-protein cycle occur by analogous mechanisms. Agonists induce hormone receptors to increase a Ga-GDP-GTP exchange and subsequent Ga 3y dissociation (GDP-a py + GTP GTP-ax + [3y + GDP) (Fig. 4). Consequently, agents that affect either the dissociation of either G or Gs, or the association of their respective as, a , or (3y subunits with adenylyl cyclase could affect rates of cAMP formation in enzyme preparations or in intact cells and tissues. There are several important examples. Gas is stably activated by poorly hydrolyzable analogs of GTP, e.g. GTPyS... 

Growth hormone. Mood disorders have been related to alterations in the activity of the growth-hormone axis. A blunted growth-hormone response to clonidine, an a2 receptor agonist, has been consistently found in depression. Increased growth-hormone secretion during the day and decreased nocturnal growth-hormone secretion have also been observed in depressed patients. Depressed patients have lower CSF concentrations of somatostatin, compared to those with schizophrenia and normal controls. While lower CSF somatostatin is a state-dependent marker of depression, it occurs in a number of unrelated nonpsychiatric conditions, and thus appears to be relatively nonspecific. 

The chemical structure of the substances capable of interacting with a determinate nuclear receptor is tremendously varied. For now no pattern exists that permits one to assure that a particular substance is going to interact with the receptor to produce an agonist or antagonist effect. In recent years the concept of endocrine disruptors has been introduced to describe the substances that are capable of modifying the endocrine equilibrium. Some of them act by binding with nuclear hormone receptors, while others interfere with the processes of regulation of hormone secretion (Lathers 2002 Melnick et al. 2002 Nakata 2002 Powles 2002 Brown et al. 2002 Sonnenschein et al. 1998). 

Zhu, C. C., Cook, L. B., and Hinkle, P. M. (2002) Dimerization and phosphorylation of thyrotropin-releasing hormone receptors are modulated by agonist stimulation. J. Biol. Chem. 277,28228-28237. 

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