ODQ

7-NI and ODQ Disturbs Memory in the Elevated Plus Maze, Morris Water Maze, and Radial Arm Maze Tests in Mice.[Pubmed:25788830]

Drug Target Insights. 2015 Mar 4;9:1-8.

Nitric oxide (NO) is an atypical neurotransmitter that causes changes in cognition. Nitric oxide synthase (NOS) and guanylate cyclase (GC) inhibitors have been shown to exert some effects on cognition in previous studies; however, the findings have been controversial. This study was aimed at understanding the effects of an NOS inhibitor, 7-nitroindazole (7-NI), and a guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), on spatial memory in modified elevated plus maze (mEPM), Morris water maze (MWM), and radial arm maze (RAM) tests. Male Balb-c mice were treated via intraperitoneal injections with 7-NI (15 mg/kg), ODQ (3, 10 mg/kg), L-arginine (100 mg/kg) + 7-NI (15 mg/kg), or physiological saline. ODQ (3 mg/kg) and 7-NI (15 mg/kg) significantly increased the second-day latency in the mEPM test. 7-NI (15 mg/kg) and ODQ (10 mg/kg) significantly increased the escape latency in second, third, and fourth sessions, decreased the time spent in the escape platform's quadrant, and increased the mean distance to the platform in the probe trial of the MWM test. ODQ (3, 10 mg/kg) and 7-NI (15 mg/kg) significantly increased the number of errors, whereas only 7-NI increased the latency in the RAM test. The administration of L-arginine (100 mg/kg) prior to 7-NI inverted the effects of 7-NI, which supports the role of NO on cognition. Our study shows that the NO/cGMP/GS pathway can regulate spatial memory in mice.

Imidazole-induced contractility of vascular smooth muscle cells in the presence of U-73122, ODQ, indomethacin and 7-nitroindazole.[Pubmed:23971197]

Pol J Vet Sci. 2013;16(2):293-7.

The aim of the study was to assess the impact of modulating factors on vascular smooth muscle cells reactivity. Vascular resistance was induced by the administration of increasing concentrations of imidazole. The experiments were performed on isolated and perfused tail artery of Wistar rats (weight 250 g - 350 g). Rats were been narcotized by urethane (intraperitoneal injection) at a dose of 120 mg/kg, stunned and then sacrificed by cervical dislocation. In the following investigation classical pharmacometric methods were used. Relationships between concentration-response curves (CRCs) for imidazole observed in the presence of ODQ [(1H-(1,2,4)oxadiazolo-[4,3-a]quinoxalin-1-one)], 7-nitroindazole and indomethacin were analyzed. Imidazole-induced contractility of vascular smooth muscle cells was independent from alpha-adrenergic receptors and PLC activity. Reactivity of VSMCsinduced by imidazole, was significantly changed in the presence of ODQ and 7-nitroindazole.

The Self- and Other-Deception Questionnaires-Intellectual Disabilities (SDQ-ID and ODQ-ID): component analysis and reliability.[Pubmed:23962604]

Res Dev Disabil. 2013 Oct;34(10):3576-82.

The objectives of this research were to: (1) investigate the component structure and psychometric properties of the Self- and Other-Deception Questionnaires-Intellectual Disabilities (SDQ-ID and ODQ-ID), (2) examine the relationship between social desirability and IQ, and (3) compare social desirability scores of those with intellectual disabilities (IDs) and a history of criminal offending to the social desirability scores of participants with IDs and those without IDs and no such history, controlling for general intellectual functioning. Men with mild to borderline IDs detained within medium secure inpatient forensic mental health services (N=40) completed the SDQ-ID and ODQ-ID at Time 1 and then two-weeks later at Time 2. Data for the men with and without IDs and no known criminal offending history were taken from a previous study (N=60). Following exploratory Principal Components Analysis, the number of questionnaire items were reduced, and a two-factor structure was found for the SDQ-ID which was labelled: (1) Positive Self Representation and (2) Denial of Intrusive Thoughts. A two-factor structure was also found for the ODQ-ID and these two factors were labelled: (1) Denial of Negative Social Interaction and (2) Untrustworthiness. Both the SDQ-ID and ODQ-ID had acceptable internal consistency and test-retest reliability. Fifteen percent of the variance in SDQ-ID scores was explained by Full Scale IQ, while 21% of the variance in ODQ-ID scores was explained by Full Scale IQ. Between group comparisons controlling for intelligence did not yield any significant differences. The shortened SDQ-ID and ODQ-ID have promising psychometric properties, and their component structures appear robust. Differences between men with and without IDs on these two measures of social desirability can be accounted for by differences in general intellectual functioning.

Effects of 7-NI and ODQ on memory in the passive avoidance, novel object recognition, and social transmission of food preference tests in mice.[Pubmed:24643075]

Med Sci Monit Basic Res. 2014 Mar 19;20:27-35.

BACKGROUND: Nitric oxide (NO) is an intercellular messenger that plays a critical role in learning and memory processes. Effects of nitric oxide synthase (NOS) inhibitors and guanylate cyclase (GC) inhibitors on cognitive function remain controversial. MATERIAL AND METHODS: The aim of this study was to investigate effects of an NOS inhibitor, 7-nitroindazole (7-NI), and a GC inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), on different aspects of memory in passive avoidance (PA), novel object recognition (NOR), and social transmission of food preference (STFP) tests. Male Balb-c mice were treated intraperitoneally with 7-NI (15 mg/kg), ODQ (3,10 mg/kg), L-arginine (100 mg/kg) + 7-NI (15 mg/kg), or physiological saline. RESULTS: ODQ (10 mg/kg) and 7-NI (15 mg/kg) significantly decreased second-day latency in PA test. 7-NI (15 mg/kg) and ODQ (10 mg/kg) significantly decreased the ratio index in the NOR test. 7-NI and ODQ (10 mg/kg) decreased cued/non-cued food eaten in STFP test. Amount of time spent in center zone significantly increased in ODQ (10 mg/kg) and 7-NI (15 mg/kg) groups in open field test, but there was no effect on total distance moved and speed of animals. ODQ (10 mg/kg) significantly increased number of entries into new compartments in exploratory activity apparatus, while 7-NI had no effect. Administration of L-arginine (100 mg/kg) before 7-NI reversed 7-NI-induced effects, supporting the role of NO in cognition. CONCLUSIONS: Our results confirm that inhibition of NO/cGMP/GS pathway might disturb emotional, visual, and olfactory memory in mice. Also, 7-NI and ODQ had anxiolytic effects in open field test, and ODQ also enhanced exploratory activity.

Comparison of two soluble guanylyl cyclase inhibitors, methylene blue and ODQ, on sodium nitroprusside-induced relaxation in guinea-pig trachea.[Pubmed:9863642]

Br J Pharmacol. 1998 Nov;125(6):1158-63.

To clarify further the role of cyclic GMP in mediating the relaxant response in guinea-pig trachea induced by sodium nitroprusside (SNP), the effects of soluble guanylyl cyclase inhibitors, methylene blue and 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ) on SNP-induced muscle relaxation and cyclic GMP accumulation were determined. SNP (0.3-100 microM) evoked a concentration-dependent relaxation of guinea-pig isolated tracheas precontracted with 0.3 microM carbachol. Preincubation of the preparations with methylene blue (10, 30 and 100 microM) resulted in a slight but concentration-dependent prevention of the relaxant response to SNP. In contrast, the relaxation to SNP was extensively prevented by 3 microM ODQ and almost abolished by 10 microM ODQ. SNP (30 microM) induced a significant elevation of cyclic GMP accumulation (from 1.34+/-0.14 to 5.39+/-0.28 pmol mg(-1) protein, n= 5; P<0.001), which was partially attenuated by 100 microM methylene blue (3.11+/-0.51 pmol mg(-1) protein, n=5; P<0.05), whereas completely abolished by 10 microM ODQ (1.31+/-0.28 pmol mg(-1) protein, n = 5; P<0.001). Methylene blue, but not ODQ and Nomega-nitro-L-arginine methyl ester (L-NAME), caused a concentration-dependent contraction in the tracheal preparation. The tension produced by 100 microM methylene blue was 41.8+/-4.3% (0.3 microM carbachol as 100%; n = 12). Moreover, the non-selective muscarinic receptor antagonist atropine and the M3-selective antagonist 4-diphenylacetoxy-N-methylpiperidine methiodine greatly inhibited the contractile effect evoked by methylene blue (100 microM). In conclusion, this study provides substantial evidence that SNP-induced muscle relaxation in guinea-pig trachea is completely via a cyclic GMP-dependent mechanism. Furthermore, ODQ, but not methylene blue, will likely become an important tool in differentiating between cyclic GMP-dependent and -independent effects of nitric oxide.

In vivo microdialysis study of a specific inhibitor of soluble guanylyl cyclase on the glutamate receptor/nitric oxide/cyclic GMP pathway.[Pubmed:8894183]

Br J Pharmacol. 1996 Oct;119(3):590-4.

1. Nitric oxide (NO) is known to stimulate soluble guanylyl cyclase, thereby eliciting an elevation of guanosine 3':5'-cyclic monophosphate (cyclic GMP) in target cells. Recently, a selective inhibitor of soluble guanylyl cyclase, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), has been identified and characterized in vitro. We have investigated the in vivo effects of ODQ on the glutamate receptor/NO/ cyclic GMP pathway by monitoring extracellular cyclic GMP during microdialysis of the cerebellum or the hippocampus of freely-moving adult rats. 2. Intracerebellar administration of ODQ (1-100 microM) via the microdialysis probe inhibited, in a concentration-dependent manner, the basal extracellular level of cyclic GMP. The maximal inhibition, measured after a 20 min perfusion with 100 microM ODQ, amounted to 80% and persisted unchanged as long as ODQ was perfused. When ODQ was removed from the perfusion stream after 20 min, the levels of cyclic GMP started to recover, suggesting reversibility of guanylyl cyclase inhibition by ODQ. 3. The cyclic GMP response evoked in the cerebellum by NMDA (200 microM) or by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA; 100 microM) was largely attenuated by 100 microM ODQ. The pattern of the inhibition curves suggests competition for guanylyl cyclase between ODQ and the NO generated by NMDA or AMPA receptor activation. 4. ODQ (100 microM) prevented the elevation of extracellular cyclic GMP levels provoked by intracerebellar infusion of the NO generator S-nitroso-N-acetylpenicillamine (SNAP; 1 mM). The inhibition of the SNAP effect was rapidly relieved when ODQ was removed from the perfusion fluid. However, ODQ (100 microM) was unable to affect the cyclic GMP response elicited by 5 mM SNAP, in keeping with the proposed idea that ODQ binds to the "NO receptor' in a reversible and competitive manner. 5. Infusion of ODQ (10, 100 or 300 microM) into the hippocampus of freely-moving rats diminished the basal extracellular level of cyclic GMP. The maximal inhibition amounted to 50% and was produced by 100 microM ODQ. 6. The cyclic GMP response observed when 1 mM SNAP was perfused in the hippocampus, similar in percentage terms to that seen in cerebellum, was dramatically reduced during co-infusion of 100 microM ODQ. 7. ODQ appears to act in vivo as a selective, reversible and possibly competitive inhibitor of the soluble guanylyl cyclase targeted by NO. This enzyme may generate most (about 80%) of the cyclic GMP found under basal conditions in the extracellular space of the cerebellum. In the hippocampus, about 50% of the basal cyclic GMP does not seem to originate from the ODQ-sensitive soluble guanylyl cyclase.

Nitric oxide-dependent long-term potentiation is blocked by a specific inhibitor of soluble guanylyl cyclase.[Pubmed:8596640]

Neuroscience. 1995 Dec;69(3):699-703.

The diffusible second messenger, nitric oxide, is synthesised in central neurons in response to activation of glutamate receptors or other stimuli that increase cytosolic Ca2+ concentrations. Among the many roles suggested for nitric oxide in the central nervous system is that of mediating synaptic plasticity. For example, long-term potentiation in the CA1 region of the rat hippocampus was reported to be blocked by inhibitors of nitric oxide synthase and exogenous nitric oxide has been claimed to induce an enduring enhancement of synaptic strength under certain conditions. These findings, however, are controversial and even when a participation of nitric oxide is evident, the transduction mechanism is unclear. A well-known action of nitric oxide is to stimulate the soluble form of guanylyl cyclase, thereby evoking an accumulation of cyclic GMP in target cells but several other mechanisms have been proposed, including stimulation of ADP ribosyltransferase or cyclooxygenase, and nitrosylation of protein thiol residues. The identification of a selective inhibitor of soluble guanylyl cyclase, the oxadiazoloquinoxaline derivative, ODQ, provides, for the first time, the means to investigate the importance of the cyclic GMP pathway in nitric oxide signal transduction. We find that ODQ and the nitric oxide synthase inhibitor, nitroarginine, reduce hippocampal long-term potentiation in an equal and mutually exclusive manner, suggesting that the actions of nitric oxide in this phenomenon are entirely mediated through cyclic GMP. The experiments also show that there is a component of long-term potentiation that involves neither nitric oxide nor cyclic GMP.

Potent and selective inhibition of nitric oxide-sensitive guanylyl cyclase by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one.[Pubmed:7544433]

Mol Pharmacol. 1995 Aug;48(2):184-8.

In brain and other tissues, nitric oxide (NO) operates as a diffusible second messenger that stimulates the soluble form of the guanylyl cylase enzyme and so elicits an accumulation of cGMP in target cells. Inhibitors of NO synthesis have been used to implicate NO in a wide spectrum of physiological and pathophysiological mechanisms in the nervous system and elsewhere. The function of cGMP in most tissues, however, has remained obscure. We have now identified a compound, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), that potently and selectively inhibits NO-stimulated guanylyl cyclase activity. In incubated slices of cerebellum, ODQ reversibly inhibited the NO-dependent cGMP response to glutamate receptor agonists (IC50 approximately nM) but did not affect NO synthase activity. The compound did not affect synaptic glutamate receptor function, as assessed in hippocampal slices, nor did it chemically inactivate NO. ODQ did, however, potentially inhibit cGMP generation in response to NO-donating compounds. An action on NO-stimulated soluble guanylyl cyclase was confirmed in studies with the purified enzyme. ODQ failed to inhibit NO-mediated macrophage toxicity, a phenomenon that is unrelated to cGMP, nor did it affect the activity of particulate guanylyl cyclase or adenylyl cyclase. ODQ is the first inhibitor that acts selectively at the level of a physiological NO "receptor" and, as such, it is likely to prove useful for investigating the function of the cGMP pathway in NO signal transduction.