Da. Schober et al., Pharmacological characterization of I-125-1229U91 binding to Y1 and Y4 neuropeptide Y/peptide YY receptors, J PHARM EXP, 293(1), 2000, pp. 275-280
Citations number
26
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
1229U91 (GW1229 or GR231118) [IIe,Glu,Pro,Dpr,Tyr, Arg,Leu,Arg,Tyr-NH2)2 cy
clic (2,4'),(2'4)-diamide] has been reported by several research groups to
be a potent antagonist at the Y1 neuropeptide Y (NPY) receptor subtype. How
ever, 1229U91 also displaces I-125-peptide YY (PYY) with high affinity from
the Y4 subtype. Previously, we reported that 1229U91 had full agonist prop
erties for the Y4 receptor. To characterize the pharmacological properties
of 1229U91 directly, we had it radioiodinated with the chloromine-T method.
I-125-1229U91 bound to cell lines expressing the human Y1 and Y4 receptors
with high affinity. The K-d and B-max for I-125-1229U91 binding to Y1 were
14.9 pM and 1458 fmol/mg protein, respectively. The Y4 receptor bound I-12
5-1229U91 with a K-d of 12.5 pM and a B-max of 1442 fmol/mg protein. When c
ompeting I-125-1229U91 binding from Y1 and Y4 receptors, a similar rank ord
er of potency was observed: 1229U91 > [Leu(31),pro(34)]-NPY greater than or
equal to [Leu(31),pro(34)]-PYY > PYY greater than or equal to NPY > NPY(2-
36) > PYY(3-36). Pancreatic polypeptide (PP) potently displaced I-125-1229U
91 from the Y4 receptor, but displayed little affinity for Y1. In autoradio
graphic studies with rat brain sections, I-125-1229U91 bound with a distrib
ution similar to that reported for the Y1 receptor when localized with I-12
5-[Leu(31),Pro(34)]-PYY. Brain regions exhibiting binding sites for I-125-P
P were not detected with this radioligand. Those include the interpeduncula
r nucleus and the periventricular nucleus of the hypothalamus. Furthermore,
I-125-labeled rat PP was not displaced from these areas with 10 nM 1229U91
. Thus, I-125-1229U91 is a high affinity Y1 and Y4 radioligand and binds wi
th a distribution in the rat brain consistent with the localization of the
Y1 receptor.