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Nearly all cells express kinin receptors that mediate the activities of both bradykinin and kallidin. The
activation of these G-protein coupled receptors causes relaxation of venular smooth muscle and
hypotension, increased vascular permeability, contraction of smooth muscle of the gut and airway
leading to increased airway resistance, stimulation of sensory neurons, alteration of ion secretion of
epithelial cells, production of nitric oxide, release of cytokines from leukocytes, and the production of
eicosanoids from various cell types [11,12]. Because of this broad spectrum of activity, kinins have been
implicated as an important mediator in many pathophysiologies including pain, sepsis, asthma,
rheumatoid arthritis, pancreatitis, and a wide variety of other inflammatory diseases. Moreover, a recent
report demonstrated that bradykinin B2 receptors on the surface of human fibroblasts were upregulated
three-fold beyond normal in patients with Alzheimer's disease, implicating bradykinin as a participant in
the peripheral inflammatory processes associated with that disease [13].
In contrast to the adverse physiologies associated with bradykinin release, there is a growing body of
literature that implicates bradykinin as a protective agent during periods of cardiac or renal stress
[14–16]. In this regard there is substantial evidence that the cardioprotective effects afforded by ACEinhibitor
treatment are a result of metabolically preserving bradykinin and are therefore mediated by
bradykinin B2 (and possibly B1) receptors [17–18]. These results point to a possible therapeutic role for
a kinin receptor agonist.
Overall, the kinins are an important part of a well-organized physiological system. The various aspects
and interdependencies of the kinin system have been, and continue to be, the focus of intensive research
efforts in many laboratories. Many pharmaceutical companies have identified this system as an ideal site
for therapeutic intervention in many inflammatory diseases. Hence, there have been many diverse
approaches taken toward the discovery of antagonists (peptide and nonpeptide) of B2 and B1 receptors.
This review focuses on the structure-based design strategies pursued in our laboratories during the past
several years.
II. Ligand-Based Investigations
A. The Solution Conformation of Bradykinin
In the late 1980s when we began the pursuit of bradykinin receptor antagonists, information of relevance
to medicinal chemists was scarce. For example, not one nonpeptide antagonist of this receptor was
known, nor were any series upon which to base a structure-activity relationship. Moreover, all
publications described bradykinin as being highly flexible in an aqueous environment, such that no
structural mimetics could be rationalized. Of course the receptors had not been cloned at that time so
nothing was known about the primary sequence of the receptor or the three-dimensional structure.
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