Synthesis and evaluation of a new series of Neuropeptide S receptor antagonists.
Administration of Neuropeptide S (NPS) has been shown to produce arousal, that is, independent of novelty and to induce wakefulness by suppressing all stages of sleep, as demonstrated by EEG recordings in rat. Medicinal chemistry efforts have identified a quinolinone class of potent NPSR antagonists that readily cross the blood-brain barrier. We detail here optimization efforts resulting in the identification of a potent NPSR antagonist which dose-dependently and specifically inhibited (125)I-NPS binding in the CNS when administered to rats.
Melamed
Jeffrey Y
JY
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA, USA. jmelamed@synthonix.com
Zartman
Amy E
AE
Kett
Nathan R
NR
Gotter
Anthony L
AL
Uebele
Victor N
VN
Reiss
Duane R
DR
Condra
Cindra L
CL
Fandozzi
Christine
C
Lubbers
Laura S
LS
Rowe
Blake A
BA
McGaughey
Georgia B
GB
Henault
Martin
M
Stocco
Rino
R
Renger
John J
JJ
Hartman
George D
GD
Bilodeau
Mark T
MT
Trotter
B Wesley
BW
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism; D006801:Humans; D007457:Iodine Radioisotopes / Q000737:chemistry; D011485:Protein Binding; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000577:Amides; D007457:Iodine Radioisotopes; C583306:NPSR-QA1 compound; D015363:Quinolones; D018013:Receptors, Neuropeptide