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[摘要]：Research in the area of simultaneously targeting more than one G protein-coupled receptor (GPCR) has increased in recent times. By exploiting the cross talk between the b2-adrenergic (b2AR) 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 b2-adrenergic and A1 adenosine bivalent parameters of linker and bifunctionality by using data that are drawn from in vitro assays. The hexyl-linked 12e (Ki, 311 nM) and butyl-linked 12c (Ki, 863 nM) bivalent compds. displayed reasonable binding affinities for the b2AR when compared with the control (-)isoproterenol (Ki, 136 nM), and both compds. also exhibited a persuasive bifunctional trend for both receptors at various drug concns. The bivalent compd. 12e was also found to have significant EC50 potency (6 nM) at the b2AR in DDT cells. |
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