Significance Voltage-gated sodium (Na v ) channels contribute to physiological and pathophysiological electrical signaling in nerve and muscle cells. Because Na v channel isoforms exhibit tissue-specific expression, subtype selective modulation of this channel family provides important drug development opportunities. However, most available Na v channel modulators are unable to distinguish between Na v channel subtypes, which limits their therapeutic utility because of cardiac or nervous system toxicity. This study describes a new class of subtype selective Na v channel inhibitors that interact with a region of the channel that controls voltage sensitivity. This interaction site may enable development of selective therapeutic interventions with reduced potential for toxicity.

The formation of new microvasculature by capillary sprouting, or angiogenesis, is a prerequisite for solid tumor growth. The genetic alterations required to activate the angiogenic program in tumor angiogenesis are still only vaguely known, but dominantly acting oncoproteins may have a much greater impact than previously realized. Here we have studied the consequences of oncogenic transformation on tumor angiogenesis in a mouse mammary carcinoma model. We provide evidence that the expression of vascular endothelial growth factor (VEGF) and of the VEGF receptor-2 (Flk-1), a signaling system centrally involved in tumor angiogenesis, occurs efficiently in tumors formed by Ras-transformed mammary epithelial cells and that both TGF-␤1 and hypoxia are potent inducers of VEGF expression in these cells. VEGF induction in the tumor periphery is mainly triggered by TGF-␤1, whereas VEGF expression in perinecrotic areas is regulated by both hypoxia and TGF-␤1. As the Rastransformed tumor cells convert into migrating, fibroblastoid cells that start to produce TGF-␤ during tumor progression, the TGF-␤ effect on VEGF expression becomes propagated throughout the tumor tissue. Thus, in progressed tumors, areas of TGF-␤1 activation and hypoxia may overlap and hence cooperate to induce VEGF expression and angiogenesis. Nevertheless, the overexpression of VEGF in non-Ras-transformed mouse mammary epithelial cells was not sufficient to promote vascularization in vivo. Based on these findings, we conclude that amongst the multiple mutations that render a normal cell tumorigenic, oncogenic Ras is a major player that in conjunction with the tumor's microenvironment sets the stage for tumor cell invasion and angiogenesis.

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Isoquinoline and quinazoline urea derivatives were found to bind to human adenosine A 3 receptors. Series of N-phenyl-N′-quinazolin-4-ylurea derivatives and N-phenyl-N′-isoquinolin-1-ylurea derivatives were synthesized and tested in radioligand binding assays on their adenosine receptor affinities. A structure-affinity analysis indicated that on the 2-position of the quinazoline ring or the equivalent 3-position of the isoquinoline ring a phenyl or heteroaryl substituent increased the adenosine A 3 receptor affinity in comparison to unsubstituted or aliphatic derivatives. Furthermore, the structure-affinity relationship of substituted phenylurea analogues was investigated. Substituents such as electron-withdrawing or electron-donating groups were introduced at different positions of the benzene ring to probe electronic and positional effects of substitution. Substitution on the 3-or 4-position of the phenyl ring decreased the adenosine A 3 receptor affinity. Substitution at position 2 with an electron-donating substituent, such as methyl or methoxy, increased human adenosine A 3 receptor affinity, whereas substitution on the 2-position with an electron-withdrawing substituent did not influence affinity. Combination of the optimal substituents in the two series had an additive effect, which led to the potent human adenosine A 3 (VUF5574, 10a) showing a K i value of 4 nM and being at least 2500-fold selective vs A 1 and A 2A receptors. Compound 10a competitively antagonized the effect of an agonist in a functional A 3 receptor assay, i.e., inhibition of cAMP production in cells expressing the human adenosine A 3 receptor; a pA 2 value of 8.1 was derived from a Schild plot. In conclusion, compound 10a is a potent and selective human adenosine A 3 receptor antagonist and might be a useful tool in further characterization of the human A 3 receptor. receptor antagonist N-(2-methoxyphenyl)-N′-(2-(3-pyridyl)quinazolin-4-yl)urea

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