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Br J Pharmacol. 2001 Mar;132(6):1179-82.

SB-334867-A: the first selective orexin-1 receptor antagonist.

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Neuroscience Research, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW.


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.

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