Design and synthesis of metabolically stable atrial natriuretic factor analogs. Amino- and carboxy-terminal stabilization.
Two analogs of rat atrial natriuretic factor, rANF7-28-NH2 and [Mpr7,Ala20,D-Arg27]rANF7-27-NH2, were prepared by the solid-phase method. These peptides had 2-fold and 7-fold less affinity, respectively, than rANF1-28 in binding to membranes prepared from cultured aortic smooth muscle cells, and both peptides were 5-fold less potent than rANF1-28 in relaxing serotonin-contracted rabbit aortic rings. rANF7-28-NH2 was rapidly degraded by rat kidney homogenates but [Mpr7,Ala20,D-Arg27]rANF7-27-NH2 had enhanced stability against rat kidney homogenate degradation. However, this in vitro stability did not translate into an extended duration of action in vivo.
Berman
J M
JM
Merrell Dow Research Institute, Cincinnati, OH 45215.
Chen
T M
TM
Sargent
R
R
Buck
S H
SH
Shea
P
P
Heminger
E F
EF
Broersma
R J
RJ
D000595:Amino Acid Sequence; D000818:Animals; D001011:Aorta / Q000378:metabolism; D009320:Atrial Natriuretic Factor / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D002462:Cell Membrane / Q000378:metabolism; D004231:Diuresis / Q000187:drug effects; D004355:Drug Stability; D007202:Indicators and Reagents; D007668:Kidney / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D009318:Natriuresis / Q000187:drug effects; D011817:Rabbits; D017461:Receptors, Atrial Natriuretic Factor; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D014664:Vasodilation / Q000187:drug effects
D007202:Indicators and Reagents; D011956:Receptors, Cell Surface; D009320:Atrial Natriuretic Factor; D017461:Receptors, Atrial Natriuretic Factor