Current Medicinal Chemistry – Immunology, Endocrine & Metabolic Agents, Volume 1, No. 3, 2001
The Design and Biological Activities of Glucagon Agonists and Antagonists, and Their Use in Examining the Mechanisms of Glucose Action Pp. 199-215
V.J. Hruby, J-M. Ahn and D. Trivedi
Vitamin D Analogs Pp. 217-234
David E. Prosser and Glenville Jones
Non Steroidal Estrogen Antagonists: Current Status and Future Perspectives Pp. 235-256
K. Hajela, A.K. Jha and J. Pandey
Elucidating Neuronal and Vascular Injury Through the Cytoprotective Agent Nicotinamide Pp. 257-267
Kenneth Maiese, Shi-Hua Lin and Zhao Zhong Chong
Therapeutic Prospects for Parathyroid Hormone and Parathyroid Hormone Analogs Pp. 269-287
P. Morley, J.F. Whitfield and G.E. Willick
[Back to top] The Design and Biological Activities of Glucagon Agonists and Antagonists, and Their Use in Examining the Mechanisms of Glucose Action
V.J. Hruby, J-M. Ahn and D. Trivedi
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.
[Back to top] Vitamin D Analogs
David E. Prosser and Glenville Jones
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 1a, 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 1a,25-(OH)2D3 for use in dermatology, cancer, osteoporosis and immunology-related conditions.
[Back to top] Non Steroidal Estrogen Antagonists: Current Status and Future Perspectives
K. Hajela, A.K. Jha and J. Pandey
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.
[Back to top] Elucidating Neuronal and Vascular Injury Through the Cytoprotective Agent Nicotinamide
Kenneth Maiese, Shi-Hua Lin and Zhao Zhong Chong
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.
[Back to top] Therapeutic Prospects for Parathyroid Hormone and Parathyroid Hormone Analogs
P. Morley, J.F. Whitfield and G.E. Willick
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 Forteoä) 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.