Arrestins in the Cardiovascular System - Progress in Molecular Biology and Translational Science - page 315

(unbiased antagonists/inverse agonists), for example, carazolol
and alprenolol.

Type 3. Ligands that induce preferential conformational activation of TM

helix VII over TM helix VI, and thus selectively activate b arrs
while blocking G proteins ( b arr-biased agonists or G-protein-
biased antagonists), for example, isoetharine and carvedilol.

Type 4. Ligands that induce preferential conformational activation of TM

helix VI over TM helix VII, and thus selectively activate
G proteins while blocking b arrs (G-protein-biased agonists or
b arr-biased antagonists), for example, MK-0354 for the niacin
receptor GPR109A. Notably, no compound of this type has been
identified for the b 2 AR to date, but nadolol ( Fig. 12.1 ) might be a
good candidate. 117,121
Considering b arr-biased agonism/antagonism at the AT 1 R, data from our
lab indicate that losartan, the prototypic AT 1 R-selective antagonist
(ARB), fails to suppress adrenal b arr1-dependent post-MI hyper-
aldosteronism, 39 a finding that prompted us to test various other structurally
similar ARBs (i.e., tetrazolo-biphenyl-methyl derivatives; Fig. 12.1 ) for
their efficacy in inhibiting the human AT 1 R- b arr interaction. Our latest
data indicate that irbesartan, like losartan, is a very weak b arr-biased antag-
onist at the AT 1 R, displaying very little (if any) “bias” for b arr inhibition
versus G protein inhibition. 59 In contrast, candesartan and valsartan are
the most potent b arr blockers at the AT 1 R and thus, the most “biased” b arr
antagonists. 59 Based on a comparison of the structures of these tetrazolo-
biphenyl-methyl derivatives, all of which are very potent G protein antag-
onists of the AT 1 R, some assumptions about the structural requirements of
AT 1 R ligands for b arr-biased antagonism can be made ( Fig. 12.1 ): (a) the
tetrazole ring attached to the biphenyl “backbone” appears essential for b arr
inhibition at the AT 1 R (as it is for G protein inhibition at the AT 1 R) and (b)
the “bulkier” the R 1 substitution of the biphenyl-methyl “backbone,” the
more “biased” the ligand is toward b arr blockade. 59 Thus, candesartan and
valsartan, which have the “bulkiest” R 1 substitutions, are the most “biased”
b arr antagonists at the AT 1 R, whereas losartan and irbesartan, which have
the “smallest” R 1 substitutions, are the least “biased” b arr antagonists. 59
As for b arr-biased agonism at the AT 1 R, our data from a series of AngII
analogs with various substitutions at amino acid position 5, all of which are
devoid of G protein activation properties due to a sarcosine ( N -methy-
l-glycine) substitution at amino acid position 1, indicate that the “bulkier”
the amino acid substitution at position 5 of the AngII peptide, the more