Synthesis of bivalent beta2-adrenergic and adenosine A 1 receptor ligands

Panagiotis Karellas, Michael McNaughton, Stephen P Baker, Peter John Scammells

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Abstract

Research in the area of simutaneously targeting more than one G protein-coupled receptor (GPCR) has increased in recent times. By exploiting the cross talk between the beta(2)-adrenergic (beta(2)AR) and adenosine A(1) receptors (A(1)AR) on adenylate cyclase activity, we synthesized a series of bivalent agonists for both GPCRs to generate responses from more than one receptor. We have demonstrated a relationship between the various beta(2)-adrenergic and A(1) adenosine bivalent parameters of linker and bifunctionality by using data that are drawn from in vitro assays. The hexyl-linked 12e (K-i, 311 nM) and butyl-linked 12c (K-i, 863 nM) bivalent compounds displayed reasonable binding affinities for the PAR when compared with the control (-)isoproterenol (K-i, 136 nM), and both compounds also exhibited a persuasive bifunctional trend for both receptors at various drug concentrations. The bivalent compound 12e was also found to have significant EC50 potency (6 nM) at the beta(2)AR in DDT cells.
Original languageEnglish
Pages (from-to)6128 - 6137
Number of pages10
JournalJournal of Medicinal Chemistry
Volume51
Issue number19
Publication statusPublished - 2008

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