Disease relevance of Tocris-1709

• CL 218,872 retarded the development of kindled seizures in a linear dose-dependent manner; rats treated with 5, 10, and 20 mg/kg, but not 1 mg/kg, of CL 218,872 required a greater number of afterdischarges (ADs) to develop generalized seizures than controls [1].
• A new chemical series was discovered, triazolopyridazines (TPZ, prototype CL 218,872), which showed anticonflict activity in rats and monkeys without sedation or ataxia and inhibited 3H-BDZ binding in brain membranes with kinetic characteristics suggesting the presence of multiple BDZ receptors [2].

Psychiatry related information on Tocris-1709

• CL 218,872 (10 mg/kg) was found to be significantly sedative in both mice and rats (i.e., both locomotor activity and head-dipping were significantly decreased) [3].
• These results suggest that the selective activation of the omega 1 receptor subtype by CL 218,872 is sufficient to produce sedation, anxiolysis, and amnesia in a manner similar to that produced by the coactivation of both the omega 1 and omega 2 receptor subtypes with diazepam [4].

High impact information on Tocris-1709

• In cerebral cortex, analysis of displacement of the benzodiazepine antagonist [3H]Ro-15-1788 by the type I-selective drug CL-218,872 reveals that PSDs contain type I benzodiazepine receptors exclusively; other subcellular fractions contain mixtures of type I and type II benzodiazepine receptors [5].
• The ID50 of the triazolopyridazine CL 218,872 was 2.3 times lower in the cerebellum than in the hippocampus [6].
• At days 10-15, both the IC50 value for CL 218,872 (near 100 nM) and the pseudo-Hill number (near 0.7) remain constant and are significantly different from the values at culture day 4 [7].
• Competition for the benzodiazepine binding site by CL 218872 indicated that cerebellar receptors were predominantly type I, adult cortical receptors were a mixture of subtypes, and neonatal cortex was enriched in type II receptor [8].
• The differentiation of a high- and low-affinity site in the cerebral cortex was corroborated by experiments in which [3H]butyl beta-carboline binding was displaced by the triazolopyridazine CL 218,872 [9].

Biological context of Tocris-1709

• Amongst novel non-benzodiazepine anxiolytics, zopiclone and CL 218,872 also produced significant increases in food intake [10].

Anatomical context of Tocris-1709

• CL 218,872 had lower affinity in spinal cord (IC50 = 825 nM) than cortex (IC50 = 152 nM), possibly reflecting the presence of fewer type 1 sites in the cord [11].
• This conclusion is further supported by the evidence that CL-218872 (5 X 10(-6) M), a specific ligand for Type I benzodiazepine recognition site, inhibited [3H]FNT binding by 50% in membranes from the above brain areas [12].
• The paleostriatum primitivum and cerebellum were enriched in receptors of the BZ type I, as indicated by their high affinity for compound CL 218872 [13].
• Analysis of BZ binding heterogeneity, using the triazolopyridazine CL 218,872 as displacing agent, indicated that binding heterogeneity exists in both the cortex and hypothalamus, whereas the cerebellum has a more homogeneous binding site population [14].
• We studied the effects of diazepam, CL 218,872, Ro 15-1788, beta-CCM and Ro 15-4513 on the gamma-aminobutyric acid-activated current in adult and newborn rat superior cervical ganglion neurons [15].

Associations of Tocris-1709 with other chemical compounds

• The numbers of 3H-flunitrazepam binding sites and their affinity was determined by Scatchard analysis of saturation isotherms and the relative abundance of type I and type II benzodiazepine receptors was assessed by drug-inhibition studies using diazepam and the triazolopyridazine, CL 218,872 [16].
• This indicates that GABA enhances CL 218,872 affinity for both type 1 and type 2 sites in both spinal cord and cerebral cortex [11].
• These results with benzodiazepines, CL 218872 and zopiclone are consistent with their anxiolytic and anticonvulsant profile in vivo and with studies of their effects upon low affinity GABA binding in vitro [17].
• In contrast, CL 218,872 and zolpidem were 4-fold more potent at inhibiting [35S]TBPS binding in adult rats relative to neonates [18].

Analytical, diagnostic and therapeutic context of Tocris-1709

• In vivo benzodiazepine receptor occupancy by CL 218,872 visualized by positron emission tomography in the brain of the living baboon: modulation by GABAergic transmission and relation with anticonvulsant activity [19].
• Type 1 benzodiazepine (BZ) binding sites in the superior temporal gyrus of schizophrenics, determined from the displacement of [3H]-FNT binding using a triazolopyridazine, CL 218,872 (200 nM), were significantly higher than in the control group [20].

References