Pharmacological implications of Bradykinins:
With such important roles in various physiological and pathological
processes the role of Bradykinins and their receptors as drug targets is
quite justifiable. The signalling of bradykinin receptors is mediated by
kinins. Following ligand-binding, B1R and B2R signal through associated
G proteins to activate signalling molecules like protein kinase C and
phospholipases, and secondary messengers like inositol-1,4,5,
-triphosphate, diacylglycerol, calcium, and arachidonic acid. These
secondary messengers go on to modulate other signalling processes (e.g.,
nitric oxide or prostaglandin production).39 Following
the discovery of bradykinin by Roche et al there are various research
that has been undertaken to exploit its role in drug development. The
invitro synthesis of BK peptide was introduced by solid phase
preparation strategy by Merrifield.40 Since then, many
kinin derivatives have been synthesized and investigated. These
sequences include modifications (e.g., amino acid substitutions,
reduction of amide bonds, N-terminal capping) that are aimed at
conferring selectivity, stability to peptidases, agonist/antagonist
properties and prolonging in vivo pharmacological
effects.41 Icatibant, a B2R antagonist, is the only
kinin to receive U.S. Food and Drugs Administration approval. It is
indicated for the treatment of acute attacks of hereditary angioedema in
adults with C1-esterase inhibitor deficiency.42Anatibant and fasitibant, B2R antagonists, advanced into clinical
testing for treatment of traumatic brain injury and knee osteoarthritis,
respectively. However, their development was discontinued due to the
lack of efficacy.43,44 The hope is that new scaffolds
will be able to find clinical utility in other disease setting
Table 1