A typical Y1 receptor regulates feeding behaviors: effects of a potent and selective Y1 antagonist, J-115814.
Neuropeptide Y (NPY) is a potent feeding stimulant. The orexigenic effect of NPY might be caused in part by the action of Y1 receptors. However, the existence of multiple NPY receptors including a possible novel feeding receptor has made it difficult to determine the relative importance of the Y1 receptor in feeding regulation. Herein we certified that the Y1 receptor is a major feeding receptor of NPY by using the potent and selective Y1 antagonist (-)-2-[1-(3-chloro-5-isopropyloxycarbonylaminophenyl)ethylamino]-6-[2-(5-ethyl-4-methyl-1,3-thiazol-2-yl)ethyl]-4-morpholinopyridine (J-115814) and Y1 receptor-deficient (Y1-/-) mice. J-115814 displaced (125)I-peptide YY binding to cell membranes expressing cloned human, rat, and murine Y(1) receptors with K(i) values of 1.4, 1.8, and 1.9 nM, respectively, and inhibited NPY (10 nM)-induced increases in intracellular calcium levels via human Y1 receptors (IC(50) = 6.8 nM). In contrast, J-115814 showed low affinities for human Y2 (K(i) > 10 microM), Y4 (K(i) = 640 nM) and Y5 receptors (K(i) = 6000 nM). Intracerebroventricular (ICV) (10-100 microg) and intravenous (IV) (0.3-30 mg/kg) administration of J-115814 significantly and dose-dependently suppressed feeding induced by ICV NPY (5 microg) in satiated Sprague-Dawley rats. Intraperitoneal (IP) administration of J-115814 (3-30 mg/kg) significantly attenuated spontaneous feeding in db/db and C57BL6 mice. Feeding induced by ICV NPY (5 microg) was unaffected by IP-injected J-115814 (30 mg/kg) in Y1-/- mice and was suppressed in wild-type and Y5-/- mice. These findings clearly suggest that J-115814 inhibits feeding behaviors through the inhibition of the typical Y1 receptor. We conclude that the Y1 receptor plays a key role in regulating food intake.
Kanatani
A
A
Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Tsukuba, Japan.
Hata
M
M
Mashiko
S
S
Ishihara
A
A
Okamoto
O
O
Haga
Y
Y
Ohe
T
T
Kanno
T
T
Murai
N
N
Ishii
Y
Y
Fukuroda
T
T
Fukami
T
T
Ihara
M
M
D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D005247:Feeding Behavior / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology*; D009765:Obesity / Q000523:psychology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors* / Q000502:physiology; D013844:Thiazoles / Q000494:pharmacology*
D001067:Appetite Depressants; C422269:J 115814; D009025:Morpholines; D011725:Pyridines; D017476:Receptors, Neuropeptide Y; D013844:Thiazoles; C097212:neuropeptide Y-Y1 receptor