Table of Contents

June 2005; 5 (3)

Speaking of Pharmacology



  • Because the rates at which therapeutics are cleared from the body can affect their effectiveness, knowing and accounting for the variables that contribute to drug clearance is of utmost importance when designing a drug dosage regimen for patients. The activities of the manifold cytochrome P450 enzymes [(CYPs), the most clinically important of which is often CYP3A] must be considered as they are essential for modification and metabolism of compounds (i.e., therapeutic, xenobiotic, etc.) prior to their excretion. To this end, much research has been expended on trying to identify and develop drug probes that accurately predict the metabolism of CYP3A substrates in individuals. Recently, Benet has written on the futility of such an enterprise; however, other researchers believe the identification of valuable predictive probes is not only possible but crucial.

  • Research on the design of compounds to selectively affect specific subsets of signals downstream of receptors has burgeoned lately, and several reports discussed at Experimental Biology 2005 indicate progress is being made in the understanding of what makes a drug functionally selective. Different conformations adopted by receptors after associating with specific ligands can determine which intracellular signaling pathways get activated and which do not. The appeal of such specific compounds is enormous when one considers that many disease states might require the subtle manipulation of some (or even one) but not all downstream events stemming from specific receptor activation. Additionally, a better understanding of functional selectivity would likely improve the drug delivery process: if compounds are screened through several functional assays appropriately designed to look for compounds exhibiting a high degree of selectivity, then many potential lead compounds might not be as frequently overlooked.

  • The effects of estrogen on responsive cells and organismic development have long been known and well documented. Estrogen binds to the estrogen receptor, a dimer of the complex translocates to the nucleus, binds specific DNA elements and regulates the transcription of particular genes, a process that takes some time to achieve. One of the curious findings of intense estrogen research—that some estrogen-dependent effects appear to occur immediately—has led to the conclusion that quick responses are mediated by an estrogen binding protein(s) in the cytoplasm or located at the plasma membrane. Hasbi et al. chart the course through which several characterized estrogen binding proteins (not necessarily sharing sequence similarity beyond the estrogen binding domain) were discovered, including most notably, the orphan G protein–coupled receptor GPR30. And what is to be made of differing accounts of GPR30’s intracellular whereabouts?


  • The anthracycline antibiotics are among the most widely used agents in treating cancer, but they tend to compromise the integrity of cardiac muscle structure and function, and risk of cardiotoxicity over time may outweigh their anticancer benefits. Intriguingly, pharmacological studies aimed at improving the chemotherapeutic efficacy of the anthracyclines have yielded important insights into the molecular workings of the cardiomyocyte. The appreciation of neuregulin/erbB signaling in cardiac tissues not only poises researchers to develop novel drug therapies, but also exhorts clinicians to explore opportunities for physiologically modulating the health of cancer patients. The molecular signaling through which physical exercise improves cardiac functioning is indeed an unforeseen lesson of anthracycline research.

  • Androgens are critical for male development and the maintenance of male secondary characteristics, including increased muscle and bone mass and spermatogenesis. The use of testosterone for hormone replacement therapy in aging men has been stymied because of unwanted effects of testosterone on the prostate and cardiovascular system. Fortunately, new research on nonsteroidal selective androgen receptor modulators (SARMs) has demonstrated their ability to stimulate or maintain muscle and bone mass but with decreased pharmacologic effects on the prostate. These compounds, as compared to androgens, have better oral bioavailability, flexibility of structural modification, androgen receptor specificity, tissue selectivity, and lack many steroid-related side effects. Other research suggests that SARMs may well prove to be effective agents in the developing field of male-directed contraception.

Beyond the Bench

Net Results