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Vol. 53, Issue 1, 128-134, January 1998
2-Selective Agonist TA-2005
Laboratory of Pharmacology and Toxicology, Graduate School of
Pharmaceutical Sciences, University of Tokyo, Hongo 7-3-1, Bunkyo-ku,
Tokyo 113, Japan
To determine the structural basis for binding subtype selective
agonists in the 
-adrenergic receptor (AR), we examined the interaction of the mutant 2AR and chimeric
1/2AR with a selective 2AR agonist, TA-2005
(8-hydroxy-5-[(1R)-1-hydroxy-2-[N-[(1R)-2-(p-methoxyphenyl)-1-methylethyl]amino]ethyl] carbostyril hydrochloride). The 2AR mutant with Ala
substituted for Ser204 (S204A) significantly decreased the affinities
for TA-2005, des-8-hydroxy-TA-2005 derivative (compound I), and
isoproterenol. In contrast, a S207A mutation slightly decreased the
affinities for TA-2005 and compound I, although the affinity for
isoproterenol was decreased dramatically. The EC50 values
of TA-2005 to activate adenylyl cyclase were not changed in either the
S204A- or S207A-2AR. In contrast with TA-2005, the
EC50 values of compound I were reduced in the
S204A-2AR but not in the S207A-2AR. These
results suggest that Ser204 is important for high affinity binding but
not necessary to activate adenylyl cyclase. Although TA-2005 was highly
selective at the 2AR, the compounds lacking
p-methoxyphenyl-ethyl (compound II) or
p-methoxyphenyl-methylethyl groups (compound III) on the amine portion of TA-2005 lost 2AR subtype selectivity.
When the second and seventh transmembrane (TM) region but not the TM1
region of the 2AR were replaced with the corresponding
regions of the 1AR, the affinities of the chimeras for
TA-2005 decreased compared with those of the wild type
2AR. Furthermore, substitution of the TM7 region of the
1AR with the corresponding region of the 2AR significantly increased the affinities for TA-2005.
The affinities for isoproterenol and compounds II and III were not
affected in the chimeras. These data suggest that the TM7 region of the
2AR plays an important role in
2-selective agonist binding. To determine the specific
amino acid which confers this high affinity binding of TA-2005 to the
2AR, an alanine-scanning mutagenesis approach was
employed. All amino acids that were different from those of the
1AR were individually changed to alanine. One mutant
receptor (Y308A-2AR) out of 10 point-mutated
2ARs showed a dramatically reduced affinity for TA-2005.
These results indicate that Tyr308 is an essential amino acid for high
affinity binding of the 2-selective agonist TA-2005.
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