Disease relevance of Tocris-0737

• In this report, we demonstrate that 2-iodomelatonin (2IMT) treatment on COS-7 cells transfected with melatonin receptors (mt1 and MT2) induces c-Jun N-terminal kinase (JNK) activation, which is pertussis toxin (PTX)-sensitive, Ras/Rac-dependent and may involve Src-family protein tyrosine kinases [1].

High impact information on Tocris-0737

• The pharmacological profile of various melatonin analogues revealed a profile (2-iodomelatonin > or = melatonin > N-acetyl serotonin > luzindole) characteristic of an ML1 subtype [2].
• 2-iodomelatonin prevents apoptosis of cerebellar granule neurons via inhibition of A-type transient outward K+ currents [3].
• Treatment with 2-iodomelatonin inhibited the IA amplitude recorded from control and apoptotic cells in a concentration-dependent manner and modified the IA channel activation kinetics of cells under control conditions [3].
• The melatonin receptor antagonist, 4P-PDOT, abrogated the effect of 2-iodomelatonin on the IK augmentation, caspase-3 activity, and apoptosis [4].
• In the case of TM VI, the substitution G271T caused substantial decrease in 2-iodomelatonin binding to the hMT2 receptor [5].

Biological context of Tocris-0737

• In each animal, high-affinity (dissociation constant approximately 40 pM) 2-iodomelatonin binding sites were observed in the hypophysial pars tuberalis, in the suprachiasmatic nucleus of the hypothalamus, and in the thalamus (paraventricular nucleus, reuniens nucleus, and nucleus of the stria medullaris) [6].
• However, 2-iodomelatonin only modified the IK-channel activation kinetics of cells under both conditions [4].
• Using 3H-thymidine incorporation assay, LNCaP cell proliferation was inhibited by 2-iodomelatonin, a high-affinity melatonin receptor agonist [7].
• Melatonin agonists induced phosphoinositide hydrolysis in melanophores in a concentration-dependent manner with a rank order of potency of 2-iodomelatonin > 6-chloromelatonin > N-acetylserotonin > melatonin [8].
• Melatonin and 2-iodomelatonin produced a significant inhibition of the PHE-induced vasoconstriction in isolated and perfused mesenteric beds (P < .001) with the same magnitude in SHR and WKY rats [9].

Anatomical context of Tocris-0737

• Pretreating cultured cells for 24 h with 2-iodomelatonin or melatonin, but not with 5-methoxytryptamine, reduced subsequent 2-[125I]iodomelatonin binding [10].
• During pharmacological screening administration of the agonists 2-iodomelatonin and 2-iodo-N-butanoyl-5-methoxytryptamine (IbMT) to the oocytes resulted in oscillatory membrane currents, whereas the administration of the MT3 agonist 5-methoxycarbonylamino-N-acetyltryptamine (GR135,531) exerted no detectable membrane currents [11].
• Melatonin and melatonin receptor agonists 2-iodo-N-butanoyl-5-methoxytryptamine and 2-iodomelatonin (1.0-100 nM) increased enterocyte [Ca(2+)](i), EC(50) of melatonin being 17.0 +/- 2.6 nM [12].
• Moreover, no superoxide anion scavenging effect of 2-iodomelatonin was observed in isolated mesenteric vascular muscle cells using lucigenin [9].
• Most ligands exhibited reversed stereoselectivity when competing with 125I 2-iodomelatonin binding to chicken retinal (ML-1) and hamster brain (ML-2) membranes, further supporting the biochemical and pharmacological differences reported for these two sites [13].

Associations of Tocris-0737 with other chemical compounds

• The in vitro proliferation of M-6 cells was significantly inhibited by melatonin and its analogues 6-chloromelatonin, and 2-iodomelatonin, at concentrations ranging from 10(-9) to 10(-4) M, as demonstrated by cell counts and measurements of DNA content [14].

Gene context of Tocris-0737

• In vitro autoradiographic assessment of melatonin receptors using 125I-labeled 2-iodomelatonin (I-MEL) revealed that melatonin receptor distribution, affinity, density, and G protein coupling are unaltered in photorefractory animals [6].

Analytical, diagnostic and therapeutic context of Tocris-0737

• Modeling has been combined with site-directed mutagenesis to investigate the role of the specific amino acid residues within the transmembrane domains (TM) numbers V, VI and VII of hMT2 receptor in the interaction with 2-iodomelatonin [5].
• The N-[2-(2-iodo-5-methoxy-1H-indol-3-yl)ethyl]acetamide (2-iodomelatonin) reported here is more useful than [3H]melatonin as a tracer in melatonin radioimmunoassay [15].

References