Aspects of Peptidomimetics - Peptide and Protein Design for Biopharmaceutical Applications - page 97

H
N

O

Bn

N

O

N
H

NH

O

O

O

N NH

O

Bn
Bn

H

O

HN

O

O N

O O H

HN

O

N

H

O NHAc F O

O

NK-2 antagonist

NK-1antagonist

Figure 3.50 Use of the somatostatin template to design an NK1 antagonist

H - Asp - Pen - Phe - D -Trp
HO - Val - Cys - Tyr - Orn

H - Glu - Thr - Pro - Asp - Cys - Phe - Trp
HO - Val - Cys - Tyr - Lys

H - Asp - Pen - Phe - Trp
HO - Val - Cys - Tyr - Lys

Urantide

urotensinII P5U

O

O

O

H 3 C

N

O

H N

NH

HN

O

O

O

N
H

O

HN N

NH

H
N Cl

N
H

H 3 C

AC-7954

NH 2 NH 2

O

S6716

O

O H

N

H

Cl

N

N

O

NH

O

Cl

N

N
Boc

Figure 3.51 Urotensin peptide analogues and mimetics

The cyclic hexapeptide Ac-c(Cys-Phe-Trp-Lys-2-Nal-Cys)-NH 2 was
identified as a potent U-II agonist. Further conformational constraint
by substituting Cys with Pen resulted in the highly potent octapeptide
agonist (P5U) Asp-c(Pen-Phe-Trp-Lys-Tyr-Cys)-Val-OH [361], and in the
antagonist urantide Asp-c(Pen-Phe- D -Trp-Orn-Tyr-Cys)-Val-OH [362],
which were shown to adopt a turn conformation. Therefore, the straight-
forward use of the somatostatin strategy resulted in the development
of a cystine-free cyclic hexapeptide agonist for the U-II receptor [363].