8106 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 26
Letters
Thus, we have designed novel cardioprotective agents
based on mechanistic and structural considerations. The
adenosine N6-substituents, cyclopentyl and 7-norbornyl,
were selected based on predictions made from the
binding affinities of the corresponding adenosine deriva-
tives22 and from the consistent effects on AR affinity of
replacing the 9-riboside moiety with a 5′-uronamido-(N)-
methanocarba-pseudoribose moiety in combination with
the 2-Cl substituent. The sum of these effects on affinity
at each of the three AR subtypes was generalized to
design new N6-cycloalkyl analogues having desired
pharmacological properties. The results of Tchilibon et
al.21 for substituted N6-benzyl and N6-(2-phenylethyl)
derivatives suggested that in each case, in comparison
to the corresponding adenine-9-riboside, the affinity at
the human A1AR decreased by at least 1 order of
magnitude while the affinity at the human A3AR tended
to increase by typically 1 order of magnitude. In the case
of N6-cyclopentyl- and N6-(7-norbornyl)adenine 9-ribo-
sides, 4 and 6, respectively,22 the affinity of each was
similar at rat and human A3ARs, but the effects of such
N6-cycloakyl substitution had not yet been probed in the
5′-uronamido-(N)-methanocarba series. The affinity of
both 9-ribosides at the human A2A and A2BARs was
weak; thus, the corresponding 5′-uronamido-(N)-metha-
nocarba derivatives were expected to be highly selective
for A1 and A3ARs in comparison to A2A and A2BARs. We
have confirmed the anticipated selectivity for the N6-
cyclopentyl derivatives 1 and 2. Also, based on the
9-ribosides, a large species difference at the A3AR
common among N6-substituted adenosine derivatives24
was predicted to be absent in the new analogues, and
this prediction was confirmed in binding assays of all
three newly synthesized derivatives.
We have examined the mixed A1/A3 agonist 2 in an
intact mouse heart model of ischemia and reperfusion
injury,6,13 in which either an A1- or A3-selective agonist
acts as a potent cardioprotective agent. The initial
findings validate the model for studying AR-dependent
protection and illustrate the highly cardioprotective
effect of 2. The role of cardiac A3ARs is complex, with
protective effects demonstrated in models of precondi-
tioning, delayed cardioprotection,13 and ischemia-rep-
erfusion.6,8 The activation of the A3AR in the rat
coronary circulation has been proposed to mediate
vasodilation.27 Also, potential side effects of adenosine
agonists, such as hypotension and sedation, must be
considered.1 Therefore, additional pharmacological ex-
amination of 2 and similar mixed agonists will be
needed.
Institute of Diabetes and Digestive and Kidney Diseases
and by RO1 HL48225 to Dr. Bruce Liang.
Supporting Information Available: Experimental de-
tails for the synthesis and biological evaluation of compounds.
This material is available free of charge via the Internet at
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In conclusion, a series of (N)-methanocarba nucleo-
sides previously characterized as selective A3AR ago-
nists has now been adapted to mixed AR selectivity
desired for cytoprotection in a variety of tissue systems.
These compounds may serve as prototypical examples
for more detailed pharmacological studies leading to the
development of novel dual acting cardioprotective AR
agonists.
Acknowledgment. We thank Dr. D. Eric Anderson
(NIDDK) for mass spectral determinations. B.V. Joshi
thanks Gilead Sciences (Foster City, CA) for financial
support. This research was supported in part by the
Intramural Research Program of the NIH, National
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