Biomedical Engineering Reference
In-Depth Information
R
R
R
R
()n
+
HN
H
N
H
COOH
H
COOH
COOH
COOH
H
2
N
COOH
3-R-Aze
3-R-Pro
3-R-Pip
R
′
R
′
R
′
()n
+
H
COOH
H
COOH
H
2
N
COOH
H
COOH
4-R-Pro
4-R-Pip
Figure 3.11 Aze, Pro and Pip chimeras
acids were incorporated into the sequences of the melanotropin analo-
gue MT-II [73], CCK, Angiotensin II, opioids [72], SP [74] and an IL-1
receptor antagonist [71]. A 4-substituted prolino-Arg analogue was
prepared from Hyp, and incorporated into atrial natriuretic peptide
analogue [75]. The chemistry of substituted pipecolic acid was recently
reviewed [76]. Several amino acid-pipecolic acid chimeras have become
available [76-78].
Considering that the side chain of aromatic amino acids can adopt
three low-energy conformations around the C
a
-C
b
bond, V. Hruby
introduced the 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid or
Tic residue to limit the conformations to gauche(
) or gauche(
þ
),
excluding the anti. According to the same reasoning, linking the
aromatic side chain to the alfa carbon, resulting in 1-amino-tetra-
lin-1-carboxylic acid (Atc), limits w
1
to the gauche(
)andanti
conformations, while the Aba residue limits w
1
to the gauche(
þ
)
and anti conformations (Figure 3.12). These three types of con-
strained amino acid therefore have complementary side-chain con-
straints (but different main-chain preferences), which makes them
very
useful
for
studying
the
conformational
preferences
during
receptor interaction [79-81].
The use of the commonly available
L
-and
D
-Tic in many bioactive
peptides has resulted in remarkable effects on affinity and selectivity and
shifts in agonist/antagonist character. V. Hruby showed that the replace-
ment of
D
-Phe
1
by
D
-Tic
1
in the cyclic somatostatin analogue CTP resulted
in a selective m-opioid agonist [25,82]. One of the most successful applica-
tions in peptide design was the development by Schiller of the TIPP family
(Tyr-Tic-Phe-Phe) of opioid peptides, resulting in very potent d-opioid
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