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.
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA, USA. jmelamed@synthonix.com
Jeffrey Y
JY
Melamed
Amy E
AE
Zartman
Nathan R
NR
Kett
Anthony L
AL
Gotter
Victor N
VN
Uebele
Duane R
DR
Reiss
Cindra L
CL
Condra
Christine
C
Fandozzi
Laura S
LS
Lubbers
Blake A
BA
Rowe
Georgia B
GB
McGaughey
Martin
M
Henault
Rino
R
Stocco
John J
JJ
Renger
George D
GD
Hartman
Mark T
MT
Bilodeau
B Wesley
BW
Trotter
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