TCS OX2 29

TCS-OX2-29 is a potent and selective OX2 receptor antagonist with IC50 of 40 nM. Displays >250-fold selectivity for OX2 over OX1. target: OX2 IC 50: 40 nM In vitro:TCS-OX2-29 shows selectivity for ion channels, and transporters (<30% inhibition at 10 μM), which includes G-protein coupled receptors associated with food intake including galanin and neuripeptide Y. [1] TCS-OX2-29 Inhibits orexin A induced IP3 accumulation and ERK1/2 phosphorylation in CHO cells transfected with the OX2 receptor. [2]

References:
[1]. Hirose M et al. N-acyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline: the first orexin-2 receptor selective non-peptidicantagonist. Bioorg Med Chem Lett, 2003 Dec 15, 13(24):4497-9. [2]. R Mould et al. Binding kinetics differentiates functional antagonism of orexin-2 receptor ligands. Br J Pharmacol. 2014 Jan; 171(2): 351-363.

Spinal Orexin-2 Receptors are Involved in Modulation of the Lateral Hypothalamic Stimulation-Induced Analgesia.[Pubmed:30877520]

Neurochem Res. 2019 Mar 15. pii: 10.1007/s11064-019-02749-w.

Role of the orexinergic system in pain modulation is well studied and involvement of the spinal orexin-1 receptors is well documented. In this study, we examined role of the spinal orexin-2 receptors in modulation of inflammatory pain in rat. Fifty-one adult male Wistar rats were implanted unilaterally with a guide cannula into the LH and intrathecal tubing in the lumbar space between L4 and L5. Chemical stimulation of LH by carbachol (250 nM/0.5 microL saline) induced remarkable analgesia during the two phases of formalin test and Intrathecal administration of different doses of TCS OX2 29 (10, 30 and 100 microM/ 0.5 microL DMSO) prior to LH stimulation, dose-dependently antagonized the antinociceptive effect of the LH-stimulation during the two phases of formalin test. The effect size of the TCS OX2 29 was eta(2) = 0.47 and eta(2) = 0. 87 for the early and late phases of the test, respectively. Also, intrathecal administration of TCS OX2 29 alone (without stimulation of the LH) had no significant effect on formalin induced pain-related behaviors. Our results showed that spinal orexin-2 receptors are involved in modulation of the LH-stimulation induced analgesia in a persistent inflammatory pain model. These findings may suggest spinal orexin-2 receptors in particular and the orexin system in general as a useful therapeutic target for treatment of chronic pains.

Intra-hippocampal administration of orexin receptor antagonists dose-dependently attenuates reinstatement of morphine seeking behavior in extinguished rats.[Pubmed:30391421]

Peptides. 2018 Dec;110:40-46.

It has been shown that the hippocampus plays an essential role in the regulation of reward and memory as indicated by the conditioned place preference (CPP) paradigm. Morphine-induced CPP is a common method to consider motivational properties of morphine in animals. Recently, this model has been used in many laboratories to investigate neuronal mechanisms underlying reinstatement of morphine seeking induced by drug re-exposure. Our previous studies indicate that the hippocampus especially CA1 region is involved in reinstatement of drug-seeking behaviors. Also, several studies have shown that orexin attenuates key functional and behavioral effects of its co-transmitter dynorphin. The present study evaluates the role of orexinergic receptors within the CA1 region of the hippocampus in the reinstatement of morphine-induced CPP. Therefore, after the extinction period, the different doses (SB 334867; 0.3, 3, and 30 nM/0.5 mul DMSO) of either orexin-1 or -2 receptor antagonists were bilaterally microinjected into the CA1, 15 min before receiving an effective priming dose of morphine (1 mg/kg). The results revealed that administration of both SB 334867 and TCS OX2 29 prior to injection of the priming dose of morphine significantly reduced the reinstatement of morphine-induced CPP without altering the animal's locomotor activity. Also, the 50% effective dose value of SB 334867 on the reinstatement of morphine seeking behavior was close three times more than that in TCS OX2 29 treatment group. Therefore, the consequences suggested that both orexin receptors in the CA1 play a considerable role in the reinstatement of morphine-induced CPP.

The effect of intracerebroventricular administration of orexin receptor type 2 antagonist on pentylenetetrazol-induced kindled seizures and anxiety in rats.[Pubmed:30103703]

BMC Neurosci. 2018 Aug 13;19(1):49.

BACKGROUND: Current antiepileptic drugs are not able to prevent recurrent seizures in all patients. Orexins are excitatory hypothalamic neuropeptides that their receptors (Orx1R and Orx2R) are found almost in all major regions of the brain. Pentylenetetrazol (PTZ)-induced kindling is a known experimental model for epileptic seizures. The purpose of this study was to evaluate the effect of Orx2 receptor antagonist (TCS OX2 29) on seizures and anxiety of PTZ-kindled rats. RESULTS: Our results revealed that similar to valproate, administration of 7 microg/rat of TCS OX2 29 increased the latency period and decreased the duration time of 3rd and 4th stages of epileptiform seizures. Besides, it significantly decreased mean of seizure scores. However, TCS OX2 29 did not modulate anxiety induced by repeated PTZ administration. CONCLUSION: This study showed that blockade of Orx2 receptor reduced seizure-related behaviors without any significant effect on PTZ-induced anxiety.

Blockade of the orexin receptors in the CA1 region of hippocampus decreased the lateral hypothalamic-induced antinociceptive responses in the model of orofacial formalin test in the rats.[Pubmed:29042271]

Peptides. 2018 Jan;99:217-222.

The role of hippocampus and lateral hypothalamus (LH) in modulation of formalin-induced nociception has been established. The present study aims to examine the role of orexin receptors in the Cornu Ammonis 1 (CA1) region of hippocampus in modulation of the LH-induced antinociception in the orofacial formalin test. Male Wistar rats were unilaterally implanted with two cannulae into the LH and CA1. Intra-LH microinjection of carbachol was done 5min after intra-CA1 administration of SB-334867 (OX1R antagonist) or TCS OX2 29 (OX2R antagonist). After 5min, 50mul of 1% formalin was subcutaneously injected into the upper lip for inducing the nociceptive behaviors. Solely intra-LH administration of carbachol reduced early and late phases of formalin-induced orofacial nociception in a dose-dependent manner. The antinociception evoked by intra-LH injection of carbachol (0.5mul of 250nM carbachol) was antagonized by intra-CA1 administration of 0.5mul of 3, 10 and 30nM solutions of SB-334867 or TCS OX2 29 during the early and late phases of orofacial formalin test. This effect was more remarkable during the late phase in comparison to the early phase. In addition, anti-analgesic effect of SB-334867 was more than TCS OX2 29 during the early and late phases. The results suggest the interpretation that a neural pathway from the LH to the CA1 probably contributes to the modulation of formalin-induced orofacial nociception through recruitment of both CA1 orexin receptors. Clinical studies are recommended to study the probable effectiveness of orexinergic system in modulation of the orofacial nociceptive responses.

Binding kinetics differentiates functional antagonism of orexin-2 receptor ligands.[Pubmed:23692283]

Br J Pharmacol. 2014 Jan;171(2):351-63.

Orexin receptor antagonism represents a novel approach for the treatment of insomnia that directly targets sleep/wake regulation. Several such compounds have entered into clinical development, including the dual orexin receptor antagonists, suvorexant and almorexant. In this study, we have used equilibrium and kinetic binding studies with the orexin-2 (OX(2)) selective antagonist radioligand, [(3)H]-EMPA, to profile several orexin receptor antagonists. Furthermore, selected compounds were studied in cell-based assays of inositol phosphate accumulation and ERK-1/2 phosphorylation in CHO cells stably expressing the OX2 receptor that employ different agonist incubation times (30 and 5 min, respectively). EMPA, suvorexant, almorexant and TCS-OX-29 all bind to the OX(2) receptor with moderate to high affinity (pk(I) values >/= 7.5), whereas the primarily OX1 selective antagonists SB-334867 and SB-408124 displayed low affinity (pK(I) values ca. 6). Competition kinetic analysis showed that the compounds displayed a range of dissociation rates from very fast (TCS-OX2-29, k(off) = 0.22 min(-)(1)) to very slow (almorexant, k(off) = 0.005 min(-)(1)). Notably, there was a clear correlation between association rate and affinity. In the cell-based assays, fast-offset antagonists EMPA and TCS-OX2-29 displayed surmountable antagonism of orexin-A agonist activity. However, both suvorexant and particularly almorexant cause concentration-dependent depression in the maximal orexin-A response, a profile that is more evident with a shorter agonist incubation time. Analysis according to a hemi-equilibrium model suggests that antagonist dissociation is slower in a cellular system than in membrane binding; under these conditions, almorexant effectively acts as a pseudo-irreversible antagonist.

N-acyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline: the first orexin-2 receptor selective non-peptidic antagonist.[Pubmed:14643355]

Bioorg Med Chem Lett. 2003 Dec 15;13(24):4497-9.

The identification of potent and selective orexin-2 receptor (OX(2)R) antagonists is described based on the modification of N-acyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline analogue 1, recently discovered during high throughput screening (HTS). Substitution of an acyl group in 1 with tert-Leucine (tert-Leu), and introduction of a 4-pyridylmethyl substituent onto the amino function of tert-Leu improved compound potency, selectivity, and water solubility. Thus, compound 29 is a promising tool to investigate the role of orexin-2 receptors.

TCS-OX2-29 is a potent, high affinities and selective orexin-2 receptor (OX2R) antagonist with an IC50 value of 40 nM and a pKI value of 7.5. TCS-OX2-29 displays ~250-fold selectivity for OX2 over OX1.

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