Antagonists, peptide, design

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. 

Attaching some short peptidic sequences to adamantane makes it possible to design novel antagonists. The bradykinin antagonist, which is used as an anticancer agent, is an example. The adamantane-based peptidic bradykinin analog was utilized in strucmre-activity relationship (SAR) studies on the bradykinin receptors and showed a potent activity in inhibition of bradykinin-induced cytokine release and stimulation of histamine release [142]. 

Salvadori S, Attila M, Balboni G, Bianchi C, Bryant SD, Crescenzi O, Guerrini R, Picone D, Tancredi T, Temussi PA, Lazarus LH. 6 Opioid-mimetic antagonists prototypes for designing a new generation of ultraselective opioid peptides. Mol Med 1995 1 678-689. 

Fig. 9. Peptidomimetic design principle of SH2 antagonists derived from a fragmentation of the native peptide ligand. The lead finding efforts discussed in Sect. 3 are classified according to the modules given above the peptide lead sequence...

Scheme 11. Development of non-peptide Src SH2 domain antagonists emerging from a computer-aided molecular design strategy... 

Recently, several groups have clinically evaluated compounds designed to increase or decrease synaptic levels of multiple neurotransmitters concurrently, such as norepinephrine plus dopamine or norepinephrine plus serotonin. The intent is to effectively treat a broader population with similar symptoms. Conversely, Merck and Pfizer s discontinuance of clinical trials of peptide Y antagonists for depression does not disprove the validation of that target until the results are better understood and can answer such questions as Was efficacy inadequate for a potent and selective compound Was selectivity of the compound for the target inadequate Does the molecular target not relate directly to the disease or have too many disconnects in the pathway to the disease ... 

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