SB-334867-A: the first selective orexin-1 receptor antagonist.
The pharmacology of various peptide and non-peptide ligands was studied in Chinese hamster ovary (CHO) cells stably expressing human orexin-1 (OX(1)) or orexin-2 (OX(2)) receptors by measuring intracellular calcium ([Ca(2+)](i)) using Fluo-3AM. Orexin-A and orexin-B increased [Ca(2+)](i) in CHO-OX(1) (pEC(50)=8.38+/-0.04 and 7.26+/-0.05 respectively, n=12) and CHO-OX(2) (pEC(50)=8.20+/-0.03 and 8.26+/-0.04 respectively, n=8) cells. However, neuropeptide Y and secretin (10 pM - 10 microM) displayed neither agonist nor antagonist properties in either cell-line. SB-334867-A (1-(2-Methyylbenzoxanzol-6-yl)-3-[1,5]naphthyridin-4-yl-urea hydrochloride) inhibited the orexin-A (10 nM) and orexin-B (100 nM)-induced calcium responses (pK(B)=7.27+/-0.04 and 7.23+/-0.03 respectively, n=8), but had no effect on the UTP (3 microM)-induced calcium response in CHO-OX(1) cells. SB-334867-A (10 microM) also inhibited OX(2) mediated calcium responses (32.7+/-1.9% versus orexin-A). SB-334867-A was devoid of agonist properties in either cell-line. In conclusion, SB-334867-A is a non-peptide OX(1) selective receptor antagonist.
Smart
D
D
Neuroscience Research, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW. Darren_2_Smart@sbphrd.com
Sabido-David
C
C
Brough
S J
SJ
Jewitt
F
F
Johns
A
A
Porter
R A
RA
Jerman
J C
JC
D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D005470:Fluorometry; D006801:Humans; D009287:Naphthyridines; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology*
C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; D009287:Naphthyridines; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D014508:Urea