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Karellas P, McNaughton M, Baker SP, Scammells PJ: Synthesis of bivalent beta2-adrenergic and adenosine A1 receptor ligands. . J Med Chem. 2008 Oct 9;51(19):6128-37. Epub 2008 Sep 11.
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 beta2-adrenergic (beta2AR) and adenosine A1 receptors (A1AR) 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 beta2-adrenergic and A1 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 beta2AR 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 beta2AR in DDT cells. |
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