Biomedical Engineering Reference
In-Depth Information
H
H
CO
-
CO
-
HN
HN
HN
CO
-
H
χ
2
H
H
H
H
H
H
H
2
N
COOH
H
2
N
COOH
Fgl
(2
S
,3
S
)-Ing
gauche(-)
gauche(+)
anti
N
χ
2
H
H
H
H
2
N
COOH
H
2
N
COOH
H
2
N
COOH
Figure 3.9 w
1
and w
2
constraints
b-turn conformation, the preferences are gauche(
) and gauche(
þ
),
respectively. The w
2
angle can also be efficiently restricted by the interac-
tion between the phenyl group in o-substituted aromatic amino acids and
the b-hydrogens (Figure 3.9). Their incorporation into the melanotropin
analogue MT-II revealed interesting effects on receptor selectivity [42].
Many applications of these topographically constrained b-substituted
amino acids in bioactive peptides such as the opioid peptides [25,34,43],
glucagon [25], somatostatin [25,30,33,44], MSH [25], CCK [25], sub-
stance P [28,29,45], DPPIV inhibitors [46] and so on have been reported.
Very interesting effects on affinity, selectivity, agonist versus antagonist
character, stability and duration of action were observed.
Whereas b-alkyl substitution provides a conformational bias at w
1
,
tethering C
a
to C
b
through an alkylidene bridge of variable length in an
amino acid results in the formation of a ring with concomitant fixation of
the side chain, depending on the relative stereochemistry of C
a
to C
b
. For
Phe this results in the 1-amino-2-phenylcycloalkanecarboxylic acid
(c
n
Phe,
n ¼
number of carbons in the ring) series. Tethering C
a
to C
g
results in 2,4-methano analogues (Figure 3.10).
R
R
R
R
()n
H
n( )
H
2
N
COOH
H
2
N
COOH
H
2
N
COOH
H
2
N
COOH
n
=
1-4
Figure 3.10 1-aminocycloalkanecarboxylic acids and 2,4-methano analogues
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