title: SB-334867-A antagonises orexin mediated excitation in the locus coeruleus.
abstract: Electrophysiological recordings from identified noradrenergic locus coeruleus (LC) neurones in rat brain slices have revealed that the orexins can cause direct and reversible depolarisation of the postsynaptic membrane. Whilst it is known that the membrane depolarisation produced by orexin-A can triple the firing rate of spontaneously active LC neurones, quantitative pharmacological analysis that determines the receptor subtype(s) mediating the orexinergic response has not yet been performed. Here we demonstrate that the effects of orexin-A are five-fold more potent than orexin-B on LC neuronal excitability. We show further that the orexin receptor antagonist SB-334867-A inhibits the effects of both agonists with pK(B) values similar to those calculated for human OX1 receptors expressed in CHO cells. Finally, we found no evidence for tonic activation of OX1 receptors in LC noradrenergic neurones despite electron microscopic evidence that orexin terminals directly contact these neurones. These data demonstrate that SB-334867-A is a useful tool compound with which to study the physiology of OX1 receptors.
authors.affiliation: Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, CM19 5AW, Essex, UK. ellen_m_soffin@gsk.com
authors.forename: E M
authors.initials: EM
authors.lastname: Soffin
authors.forename: M L
authors.initials: ML
authors.lastname: Evans
authors.forename: C H
authors.initials: CH
authors.lastname: Gill
authors.forename: M H
authors.initials: MH
authors.lastname: Harries
authors.forename: C D
authors.initials: CD
authors.lastname: Benham
authors.forename: C H
authors.initials: CH
authors.lastname: Davies
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004594:Electrophysiology; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008125:Locus Coeruleus / Q000187:drug effects*; D008297:Male; D009287:Naphthyridines; D009479:Neuropeptides / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D064446:Orexin Receptors; D000068797:Orexins; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism; D018013:Receptors, Neuropeptide; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology*
chemical_list: C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; D002352:Carrier Proteins; C000596229:HCRT protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009287:Naphthyridines; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D043562:Receptors, G-Protein-Coupled; D018094:Receptors, Metabotropic Glutamate; D011976:Receptors, Muscarinic; D018013:Receptors, Neuropeptide; D014508:Urea