-transparent.png){kind=logo}
We have designed and synthesized several cyclic disulfide-containing peptide analogues of dynorphin A (Dyn A) which are conformationally constrained in the putative "address" segment of the opioid ligand. Several of these Dyn A analogues exhibit unexpected selectivities for the kappa and mu opioid receptors(s) of the central vs peripheral nervous systems. Thus, incorporation of conformational constraint in the putative "address" segment of Dyn A analogues has resulted in the kappa/mu opioid receptor ligands [Cys5,Cys11]Dyn A1-11-NH2 (1) and [Cys5,Cys11,D-Ala8]Dyn A1-11-NH2 (2), which possess high kappa and mu opioid receptor affinities centrally (guinea pig brain, GPB), but only weak activity at peripheral kappa and mu opioid receptors (guinea pig ileum, GPI). On the other hand, [Cys8,Cys13]Dyn A1-13-NH2 and [D-Cys8,D-Cys13]Dyn A1-13-NH2 (5) display high kappa potencies and selectivities at the peripheral (GPI) but not at the central (GPB) kappa opioid receptor. The lack of correlation between the pharmacological profiles observed in smooth muscle and in the brain binding assays suggests the existence of different subtypes of the kappa and mu opioid receptors in the brain and peripheral nervous systems.
A M Kawasaki, and
R J Knapp, and
T H Kramer, and
W S Wire, and
O S Vasquez, and
H I Yamamura, and
T F Burks, and
V J Hruby
November 1994,
Journal of medicinal chemistry,
A M Kawasaki, and
R J Knapp, and
T H Kramer, and
W S Wire, and
O S Vasquez, and
H I Yamamura, and
T F Burks, and
V J Hruby
November 2005,
The journal of peptide research : official journal of the American Peptide Society,
A M Kawasaki, and
R J Knapp, and
T H Kramer, and
W S Wire, and
O S Vasquez, and
H I Yamamura, and
T F Burks, and
V J Hruby
April 2002,
Biochemical and biophysical research communications,
A M Kawasaki, and
R J Knapp, and
T H Kramer, and
W S Wire, and
O S Vasquez, and
H I Yamamura, and
T F Burks, and
V J Hruby
August 2003,
Angewandte Chemie (International ed. in English),
A M Kawasaki, and
R J Knapp, and
T H Kramer, and
W S Wire, and
O S Vasquez, and
H I Yamamura, and
T F Burks, and
V J Hruby
January 2007,
Chemistry (Weinheim an der Bergstrasse, Germany),
A M Kawasaki, and
R J Knapp, and
T H Kramer, and
W S Wire, and
O S Vasquez, and
H I Yamamura, and
T F Burks, and
V J Hruby
November 1994,
Journal of medicinal chemistry,
A M Kawasaki, and
R J Knapp, and
T H Kramer, and
W S Wire, and
O S Vasquez, and
H I Yamamura, and
T F Burks, and
V J Hruby
September 2006,
Journal of peptide science : an official publication of the European Peptide Society,
A M Kawasaki, and
R J Knapp, and
T H Kramer, and
W S Wire, and
O S Vasquez, and
H I Yamamura, and
T F Burks, and
V J Hruby
August 2000,
Journal of medicinal chemistry,
A M Kawasaki, and
R J Knapp, and
T H Kramer, and
W S Wire, and
O S Vasquez, and
H I Yamamura, and
T F Burks, and
V J Hruby
May 1990,
International journal of peptide and protein research,
A M Kawasaki, and
R J Knapp, and
T H Kramer, and
W S Wire, and
O S Vasquez, and
H I Yamamura, and
T F Burks, and
V J Hruby
November 2002,
Bioorganic & medicinal chemistry letters,
