Binding domains of the β-adrenergic receptors for β1 and β2- selective agonists

Structural basis of the β-adrenergic receptor (βAR) to confer the β selectivity is largely unknown. We investigated the binding regions of βAR which is important for the subtype selective binding. TA-2005 is a highly selective β² agonist with the carbostyril structure. Binding regions of the βAR for TA-2005 was investigated by use of chimeric β₁ and β₂ receptors as compared with those of non-selective β agonist isoproterenol. Replacement of transmembrane region 2 (TM2) or TM7 of β₂AR with those of β₁AR decreased the affinity of TA-2005. Deletion of methoxyphenyl group from TA- 2005 molecule lost β₂ selectivity. Then it is reasonable to assume that methoxyphenyl group interacts with TM2 and TM7 of β₂AR, and contributes to the β₂ selectivity. Several β₂ selective agonists including formoterol and salmeterol also required TM2 or TM7 for the β₂ selective binding. T- 0509 is a β₁ selective full agonist. In contrast with the binding of β₂ selective agonist, selective binding of T-0509 to β₁AR required the only TM2 of β₁AR. These data suggested that TM2 and TM7 of βAR is important for the subtype selective binding.