SB-334867 hydrochloride

SB-334867 is a selective antagonist of orexin-1 receptor [1].

Orexin-A and orexin-B are two peptides isolated from rat hypothalamus. They are involved in some physiological functions such as the control of feeding, energy metabolism and regulation of the sleep-wake cycle. SB-334867 can inhibit the orexin-A and orexin-B induced calcium responses in CHO-OX1 cells with pKB values of 7.27 and 7.23, respectively. SB-334867 is more selective for OX1 receptor over OX2 receptor. It causes 32.7% and 22% inhibition of orexin-A and orexin-B induced calcium responses in CHO-OX2 cells, respectively. Moreover, SB-334867 is found to reduce both orexin-A-induced and fasting-induced food intake. The acute anorectic effect of it is associated with signi®cant reductions in all active behaviours [1, 2].

References:
[1] Smart D, Sabido-David C, Brough S J, et al. SB-334867-A: the first selective orexin-1 receptor antagonist. British journal of pharmacology, 2001, 132(6): 1179-1182.
[2] Rodgers R J, Halford J C G, Nunes de Souza R L, et al. SB-334867, a selective orexin-1 receptor antagonist, enhances behavioural satiety and blocks the hyperphagic effect of orexin-A in rats. European Journal of Neuroscience, 2001, 13(7): 1444-1452.

SB 334867, a selective orexin receptor type 1 antagonist, elevates seizure threshold in mice.[Pubmed:26916826]

Life Sci. 2016 Apr 1;150:81-8.

AIM: Orexins A and B are hypothalamic neuropeptides involved in a number of physiological and behavioral processes. They work via OX1 and OX2 receptors. Recent studies revealed that orexins may be implicated in seizure activity. Therefore, the present study was undertaken to evaluate the influence of SB 334867 (a selective OX1 receptor antagonist) and EMPA (a selective OX2 receptor antagonist) on the seizure thresholds in mice. We also aimed to determine the changes of orexin A level following different types of seizures. MAIN METHODS: The intravenous pentylenetetrazole (i.v. PTZ) seizure test, the maximal electroshock seizure threshold (MEST) test and the 6 Hz seizure test were used in the present study. Brain orexin A level was determined via enzyme-linked immunoassay (ELISA). KEY FINDINGS: SB 334867 did not affect the seizure threshold for myoclonic twitches and tonic seizures in the i.v. PTZ seizure test. This compound, however, significantly raised the threshold for the PTZ-induced clonic seizures, for tonic hindlimb extension in the MEST test as well as for psychomotor seizures induced by 6 Hz stimulation. In comparison, EMPA did not alter the seizure thresholds in the i.v. PTZ test. Both EMPA and SB 334867 did not affect motor coordination and muscular strength. ELISA showed the increase of total brain orexin A level following different types of seizures. SIGNIFICANCE: Our results provide further evidence for the role of orexins in seizure activity and suggest that pharmacological blockade of the OX1 receptors may represent a novel therapeutic approach in the treatment of seizure disorders.

Intra-LC microinjection of orexin type-1 receptor antagonist SB-334867 attenuates the expression of glutamate-induced opiate withdrawal like signs during the active phase in rats.[Pubmed:27816550]

Neurosci Lett. 2017 Jan 1;636:276-281.

Opiate withdrawal syndrome is temporally associated with the hyperactivity of locus coeruleus neurons. Previous studies have shown that this hyperactivity, at least in part, results from the activity of excitatory afferents which mainly include the orexinergic neurons of hypothalamus and glutamatergic neurons of paragigantocellularis (PGi) nucleus. The effect of intra LC orexin type 1 receptor antagonism was investigated on expression of glutamate-induced morphine withdrawal-like signs in rats. Regarding the involvement of both orexin and LC in modulation of circadian rhythm, experimental procedures were performed during the rest (day) and the active (night) phases. Male Wistar rats (250-300g) received escalating doses (6, 16, 26, 36, 46, 56, 66mg/kg, 2ml/kg) of morphine sulfate subcutaneously for 7days. Then, glutamate (100nM, 200nl) was microinjected into the LC region and the subsequent behavioral manifestations were visually monitored in both rest and active phases. SB-334867 (as a selective orexin type 1 receptor antagonist) was microinjected into the LC prior to glutamate administration. Results indicate that intra-LC microinjection of glutamate elicits morphine withdrawal-like behavioral signs in rats. It is noteworthy that this effect was significantly suppressed in rats pretreated with SB-334867 only during the active phase. It could be concluded that orexin-A plays a role in expression of glutamate-induced opiate withdrawal-like signs and differential orexinergic tone during the rest and active phases might explain the observed difference in activity of LC neurons.

SB-334867, an orexin receptor 1 antagonist, decreased seizure and anxiety in pentylenetetrazol-kindled rats.[Pubmed:27739093]

Fundam Clin Pharmacol. 2017 Apr;31(2):201-207.

Convulsive seizures are due to abnormal synchronous and repetitive neuronal discharges in the central nervous system (CNS). Finding new therapeutics to overcome the side effects of the current drug therapies and to increase their effectiveness is ongoing. Orexin-A and orexin-B are brain neuropeptides originating from postero-lateral hypothalamic neurons. Studies show that orexins, through activation of OX1 and OX2 receptors, have excitatory effects in the CNS. Accordingly, this study was designed to evaluate the effect of OX1 receptor antagonist (SB-334867) on seizure- and anxiety-related behaviors of pentylenetetrazol (PTZ)-kindled rats. Kindling was induced by repeated intraperitoneal (IP) injections of PTZ (32 mg/kg) with two-day intervals for 24 days in male Wistar rats. Three groups received intracerebroventricular (ICV) injections of SB-334867 (2.5, 5, and 10 mug/rat) before PTZ injections. Two control groups received vehicle (2 muL/rat, ICV) and valproate (26 mug/rat, ICV) before PTZ injections. An extra group of control animals received saline both ICV and IP. Seizure-related behaviors were monitored for 30 min following PTZ administration. The anxiety-like behaviors were also assessed using elevated plus-maze in the first and last days of the study. The results revealed that ICV injection of SB-334867, mainly at the dose of 10 mug/rat, decreased the median of seizure stages, prolonged the latency and reduced the duration of different seizure stages, and reversed the PTZ-induced anxiety-like behaviors. Based on the presented results, it is suggested that pharmacological blockade of the OX1 receptor is a potential target in the treatment of seizure and concomitant anxiety disorders.

Effect of Orexin A antagonist (SB-334867) infusion into the nucleus accumbens on consummatory behavior and alcohol preference in Wistar rats.[Pubmed:26997723]

Indian J Pharmacol. 2016 Jan-Feb;48(1):53-8.

OBJECTIVE: Nucleus accumbens (NAcc) has a role in addiction and ingestive behavior. In order to assess orexinergic system involved in this, we infused Orexin A antagonist and assessed the effect on food intake fluid intake and alcohol preference in Wistar rats. MATERIALS AND METHODS: Inbred Wistar rats (n = 54) were divided into control and experimental groups (low dose and high dose). Using stereotaxic method, guide cannula was set in place bilaterally to reach NAcc. Low dose (3 ng) and high dose (6 ng) of Orexin A antagonist (SB-334867) was infused, and the food consumption, water intake and alcohol intake, and two bottle free choice preference test for alcohol were carried out in the experimental group. The control group received saline infusion and rest of the methods followed were same. The measurements were carried out immediately after the infusion, at 1 h, 2 h, 4 h, and for the whole day and represented in the figure and tables. RESULTS: A decrease in water intake observed immediately after the infusion in 1(st) h (P < 0.05) and 2(nd) h (P < 0.01), which was more in high dose group compared to low dose and controls. Alcohol intake was also following the same pattern. In two bottle free choice, rats did not show any specific preference to alcohol. CONCLUSION: There was dose dependent reduction in intake of food and fluids in treated rats. This suggested a possible role for orexinergic system in ingestive behavior. However, Orexin A may not have a role in modulation of alcohol addiction by the rewarding center NAcc.

SB-334867 (SB 334867A) is an excellent,selective and blood–brain barrier permeable orexin-1 (OX1) receptor antagonist, shows selectivity over OX2 (pKb=7.4), 100-fold over 5-HT2B, 5-HT2C with pKi values of 5.4 and 5.3, respectively. SB-334867 reduces ethanol consumption and inhibits the acquisition of morphine-induced sensitization to locomotor activity in vivo.

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