Versatile Estrogen Receptors
Nuclear receptors can be promiscuous, that is, can react with multiple ligands. “I prefer to call that eclectic behavior,” said John A. Katzenellenbogen, professor, department of chemistry, University of Illinois at Urbana-Champaign.
“The estrogen receptor is an example of a receptor that plays diverse roles. Estrogen receptors are rather remarkable in being expressed not only in reproductive tissues such as the uterus and breast but also in the cardiovascular system, the lung, and the brain. This can be helpful or deleterious with regard to therapies. The breast cancer inhibitor tamoxifen blocks the estrogen receptor but unfortunately also stimulates the uterus.
“Our knowledge of the structure and function of nuclear receptors continues to grow. The old lock-and-key concept has evolved to a more sophisticated level in that we are now looking at the cross-talk among receptors and their exquisite ability to accommodate different ligand structures. Using medicinal chemistry approaches, we have found that rather unusual structures can surprisingly result in enhanced selectivity.”
Dr. Katzenellenbogen was recently part of a collaboration with Christopher K. Glass of the University of California School of Medicine, San Diego, that found ligands capable of exerting neuroprotective effects in a subset of estrogen receptors in microglia and astrocytes.
“These cells are found primarily in neural tissue and play a role in the maintenance of homeostasis and responses to infection and cellular injury. We provided a set of our ligands and saw that different ligands affected inflammation differently.
“Aside from in vitro assays, these neuroprotective effects extended to an animal model of multiple sclerosis—i.e., murine experimental autoimmune encephalomyelitis. We hope to continue studies with these ligands that we feel have a potential for therapeutic development.”
Dr. Katzenellenbogen cautioned that “overall, these studies show how specific chemical modifications in ligands can have different effects for the better or for the worse. Ultimately, as we better understand how ligands fit into their various receptors, we hope to be able to design improved drugs with reduced untoward effects.”