Differential antagonism of amylin's metabolic and vascular actions with amylin receptor antagonists.
High affinity amylin binding sites are present in the rat nucleus accumbens. These sites bind [125I]amylin with an affinity of 27 pM and have high affinity for salmon calcitonin (sCT) and moderately high affinity for calcitonin gene related peptide (CGRP). N-terminally truncated peptides were tested for their ability to compete for [125I]amylin binding to these sites and to antagonize the metabolic and vascular actions of amylin. CGRP(8-37), sCT(8-32), and ac-[Asn30,Tyr32]sCT(8-32) (AC187) inhibited [125I]amylin binding to rat nucleus accumbens. Order of potency at inhibiting amylin binding (AC187 > sCT(8-32) > CGRP(8-37)) differed from the order of potency at inhibiting [125I]CGRP binding to SK-N-MC neuroblastoma cells (CGRP(8-37) > AC187 > sCT(8-32)) . AC187 was the most potent antagonist of amylin's effects on isolated rat soleus muscle glycogen metabolism, and it was more effective than either sCT(8-32) or CGRP(8-37) at reducing amylin-stimulated hyperlactemia in rats. In contrast, CGRP(8-37) was the most potent peptide at antagonizing amylin-induced hypotension in rats. Amylin's hypotensive actions appear to be mediated by a weak action at CGRP receptors, while its metabolic actions are mediated by receptors with a distinct antagonist profile. AC187 is a potent antagonist of amylin binding sites in nucleus accumbens and of amylin's metabolic actions.
Beaumont
K
K
Amylin Pharmaceuticals Inc., San Diego, CA 92121, USA.
Moore
C X
CX
Pittner
R A
RA
Prickett
K S
KS
Gaeta
L S
LS
Rink
T J
TJ
Young
A A
AA
D000682:Amyloid / Q000037:antagonists & inhibitors*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D066298:In Vitro Techniques; D058228:Islet Amyloid Polypeptide; D007773:Lactates / Q000097:blood; D019344:Lactic Acid; D008297:Male; D009132:Muscles / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments; D010455:Peptides / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D058287:Receptors, Islet Amyloid Polypeptide; D018000:Receptors, Peptide / Q000037:antagonists & inhibitors*
D000682:Amyloid; D058228:Islet Amyloid Polypeptide; D007773:Lactates; D010446:Peptide Fragments; D010455:Peptides; D058287:Receptors, Islet Amyloid Polypeptide; D018000:Receptors, Peptide; C087166:AC 187; D019344:Lactic Acid