Current Medicinal Chemistry - Immunology, Endocrine & Metabolic Agents - Volume 1, Issue 3, 2001

Glucagon is a crucial hormone in glucose homeostasis and hence has great potential for application to research which seeks to understand its role in normal and diabetic states. Furthermore, antagonists of glucagon, acting at the glucagon receptor, have numerous applications for studying glucagon's role in various physiological functions, and as a potential drug for the treatment of diabetes and diabetic syndromes. In this paper we will discuss research done over the last decade or so which has led to development of 1) the first pure glucagon receptor antagonists which have no partial agonist activity even at high concentrations and under conditions where the cAMP signal is greatly enhanced 2) systematic studies of glucagon structure-function which have greatly extended our knowledge of those amino acids in glucagon which are most responsible for high affinity binding 3) residues most important for agonist and for antagonist biological activities 4) the first highly truncated analogues of glucagon which possess high affinity for the glucagon receptor and are antagonists 5) cyclic analogues of glucagon which provide insight in the role of a-helix and b-turn structures in the binding affinity of glucagon to its receptor 6) the first glucagon analogues with subnanomolar binding at the glucagon receptor and 7) insights into those stereostructural properties which are different in agonist and antagonist analogues. We also discuss conformational studies which have been performed on glucagon and its agonist and antagonist analogues using various biophysical methods including NMR, X-ray crystallography and circular dichroism spectroscopy. Finally we briefly discuss the uses of glucagon analogues, especially glucagon antagonists, in examining the mechanisms and roles of glucagon in normal and diabetic states, and some aspects of the molecular biology of the glucagon receptor.

Analogs of vitamin D constitute a class of pharmacological agents with calcium-regulating and cell-differentiating properties. They are designed to directly or indirectly mimic the actions of the naturally occurring hormone 1α , 25-(OH)2D3. Since this molecule is activated and inactivated by cytochrome P450-mediated hydroxylation, these steps can be circumvented or blocked in vitamin D analog and prodrug design. All natural and synthetic analogs are currently believed to work through a nuclear receptor (VDR)-mediated transactivation process which serves to regulate the expression of variety of proteins at the gene transcriptional level. There is optimism that “tweaking” the vitamin D molecule structure will provide analogs with selective actions of 1α,25-(OH)2D3 for use in dermatology, cancer, osteoporosis and immunology-related conditions.

The development of compounds that can counteract the biological effects of estrogens has drawn a lot of attention over the last several decades. Such compounds termed as estrogen antagonists or antiestrogens are of considerable interest both in pharmaceutical industry as well as in academic research groups as potential therapeutic agents. A large number of Non Steroidal molecules belonging to diverse classes such as stilbenes, ethanes, 2-phenyl indoles, phenylindenes, benzofurans, benzothiophenes, triarylethylenes, triarylpropenones and more recently 2,3-diaryl benzopyrans have shown estrogen antagonistic activities. They have found several clinical applications like clomiphene in the treatment of endocrine disorders and due to relative or absolute hormone excess, tamoxifen and its derivatives toremifene, droloxifene, idoxifene are being used to treat hormone dependent cancers chiefly breast cancer, raloxifene, for the prevention and treatment of post menopausal osteoporosis and most importantly ormeloxifene or centchroman as the first nonsteroidal post-coital contraceptive because of its ability to antagonize estrogen action in the uterus by interfering with endogenous hormone during the pre-implantation and post implantation phases of reproduction. The clinical success of these molecules coupled with the novel finding of tissue selectivity exhibited by some recent molecules has once again refocused the attention of chemist and biologists on the development of estrogen hormone antagonists as selective target of tissue specific drugs. Many new nonsteroidal antagonists like EM-800, CP-336156, GW-5638, arzoxifene are in various stages of clinical development as tissue selective estrogen receptor modulators.

Both neuronal and cerebrovascular endothelial cell (EC) injury are intimately involved in the development of acute and chronic neurodegenerative disorders. Recently, this cellular injury has been shown to consist of two distinct pathways of programmed cell death (PCD) that involve the degradation of genomic DNA and the exposure of membrane phosphatidylserine (PS) residues. In addition, it is the downstream cellular and molecular cascades that are considered to be the vital for the prevention and reversal of neuronal and vascular injury. These include free radical injury, the independent mechanisms of programmed cell death, loss of mitochondrial membrane potential, release of cytochrome c, DNA repair enzymes, changes in intracellular pH, endonuclease activation, cysteine protease generation, and MAP kinase activation. As a novel cytoprotectant, the agent nicotinamide can maintain DNA integrity and prevent the progression of membrane PS exposure. Immediate and delayed injury paradigms with nicotinamide also illustrate the ability of this agent to maintain mitochondrial membrane potential, prevent specific cysteine protease activation, and reverse a previously sustained insult. As an investigational tool, nicotinamide has assisted in identifying several of the cellular pathways that modulate ischemic neuronal and vascular injury and has offered new therapeutic strategies for central nervous system degenerative disorders.

Parathyroid hormone (PTH) is an 84-amino acid peptide produced by the parathyroid glands that regulate calcium homeostasis through actions on the kidney, intestine and bone. PTH's actions are mediated through a family of receptors that activate the adenylyl cyclase and / or phospholipase Cb signaling pathways. These receptors are widely expressed and hence present opportunities for the development of therapeutics for a wide variety of indications. The clinical development of PTH is most advanced for the treatment of postmenopausal osteoporosis. Osteoporosis is a disease characterised by low bone mass, structural deterioration of bone and increased risk of fracture. All currently approved therapies for osteoporosis (e.g., estrogen, bisphosphonates, calcitonin and selective estrogen receptor modulators) are antiresorptive agents that suppress osteoclasts to allow osteoblasts to fill in existing remodelling space and prevent further bone loss. Intermittent, low-dose PTH therapy leads a new class of bone anabolic agents capable of going beyond just filling in existing remodelling space and building strong new bone in patients with established osteoporosis who are at high risk of fracturing. Recombinant hPTH-(1-34) (also called Teriparatide or Forteoa) has completed Phase III clinical trials and is under regulatory review by the United States Food and Drug Administration. The native hPTH-(1-84) and novel small PTH analogs are close behind in development. New data are emerging which suggest that injected PTHs may also be used to restore bone loss resulting from immobilisation, exposure to microgravity or excessive glucocorticoid use, and to promote fracture healing. Topical PTH is also being assessed as a treatment for psoriasis.