SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF NEW POTENTIAL ANTAGONISTS OF B1 RECEPTOR

• Grant number: 08/08517-4
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: November 01, 2008
• End date: June 30, 2009
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Suma Imura Shimuta
• Grantee: Adriana de Carvalho Mesquita
• Host Institution: Departamento de Biofísica. Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Cloning of the kinin B1 and B2 receptors revealed that they belong to the superfamily of seven transmembrane-spanning G protein coupled receptors. The B2 receptor is expressed in almost all cell types and several pharmacological studies have led to synthesis of a series of antagonists displaying high affinity for this type of receptor. The B1 receptor is less studied and is generally absent in healthy tissue, but its expression is rapidly induced in pathological conditions. It has been shown that in mice treated with antagonists or with targeted deletion of this B1 receptor, the hypotensive responses to bacteria lipopolyssacharide (LPS) injection is blunted and there is reduction in invasion of polymorphonuclear leukocytes in unjured tissues and hypoalgesia, indicating an important role played by B1 receptor in pathophysiological processes. It is noteworthy that the classic antagonist of the B1 receptor, DesArg9Leu8BK (DLBK) behaved as an agonist in the ileum isolated from rat. The aim of this study was to further evaluate two analogs of DBLK: 9-fluorenylmethoxycarbonyl (Fmoc)-DLBK, by attatching a volumous and lipophylic substituent Fmoc and DesArg9Leu8BK-CONH2 for their activities. These peptides will be evaluated in strips of ileum isolated from rats which constitutively expresses kinin B1 and B2 receptors.