Pharmacological evaluation of 1229U91, a novel high-affinity and selective neuropeptide Y-Y1 receptor antagonist.
The physiological role of neuropeptide Y (NPY), peptide YY (PYY) and their receptors (Y1 and Y2) has been difficult to elucidate mainly due to the lack of selective and high-affinity antagonists. Recently, Burroughs Wellcome disclosed a series of cyclic peptides, including the compound 1229U91, which were reported to be selective NPY receptor antagonists (PCT Publication No. WO 94/00486). The objective of this study was to evaluate the pharmacological properties of 1229U91. In radioligand binding studies, 1229U91 displaced specifically bound [125I]PYY from SK-N-MC cells (Y1 receptors) and SK-N-BE(2) cells (Y2 receptors) yielding pKi +/- S.E.M. estimates of 10.9 +/- 0.2 and 7.9 +/- 0.2, respectively. In the isolated perfused kidney of rat (Y1 receptor assay), NPY (10-1000 ng, bolus injection) evoked concentration-dependent increases in perfusion pressure (EC50 = 54.5 ng). In this assay, 1229U91 (1, 10 and 100 nM) produced concentration-dependent dextral displacement of the concentration-effect curve to NPY. The antagonism was surmountable at 1 nM 1229U91 (apparent pA2 estimate +/- S.E.M. = 9.3 +/- 0.4). At concentrations of 10 and 100 nM, 1229U91 produced significant depression of the maximum response to NPY (36 and 67%, respectively). In the vas deferens of rat (Y2 receptor assay), 1229U91 (3 microM) had no effect on NPY-induced inhibition of electrically evoked twitch response. In pithed rats, 1229U91 (0.3, 1 and 3 micrograms/kg/min i.v.) produced dose-dependent dextral displacement of the pressor dose-response curve to NPY yielding dose-ratio estimates of 2.4, 25.4 and 57.5, respectively. 1229U91 (3 micrograms/kg/min i.v.) had no effect on the pressor responses to norepinephrine or angiotensin II.(ABSTRACT TRUNCATED AT 250 WORDS)
Hegde
S S
SS
Roche Bioscience, Palo Alto, California, USA.
Bonhaus
D W
DW
Stanley
W
W
Eglen
R M
RM
Moy
T M
TM
Loeb
M
M
Shetty
S G
SG
DeSouza
A
A
Krstenansky
J
J
D000595:Amino Acid Sequence; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002460:Cell Line; D003655:Decerebrate State; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D009478:Neuropeptide Y / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000378:metabolism / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors*; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
C097287:1229U91; D007457:Iodine Radioisotopes; D009478:Neuropeptide Y; D010456:Peptides, Cyclic; D017476:Receptors, Neuropeptide Y; D000804:Angiotensin II; D009638:Norepinephrine