The hydrophobic tunnel present in LOX-1 is essential for oxidized LDL recognition and binding.

Lectin-like oxidized LDL (ox-LDL) receptor-1 (LOX-1) is a type-II transmembrane protein that belongs to the C-type lectin family of molecules. LOX-1 acts as a cell surface endocytosis receptor and mediates the recognition and internalization of ox-LDL by vascular endothelial cells. Internalization of ox-LDL by LOX-1 results in a number of pro-atherogenic cellular responses implicated in the development and progression of atherosclerosis.

The synthesis of highly potent, selective, and water-soluble agonists at the human adenosine A3 receptor.

Using a combination of parallel and directed synthesis, the discovery of a highly potent and selective series of adenosine A3 agonists was achieved. High aqueous solubility, required for the intended parenteral route of administration, was achieved by the presence of one or two basic amine functional groups.

Novel N6-substituted adenosine 5'-N-methyluronamides with high selectivity for human adenosine A3 receptors reduce ischemic myocardial injury.

We recently reported the identification of a novel human adenosine A3 receptor-selective agonist, (2S,3S,4R,5R)-3-amino-5-[6-[5-chloro-2-(3-methylisoxazol-5-ylmethoxy)benzylamino]purin-9-yl]-4-hydroxytetrahydrofuran-2-carboxylic acid methylamide (CP-608,039), with 1,260-fold selectivity for the human A3 versus human A1 receptor (DeNinno et al., J Med Chem 46: 353-355, 2003). However, because the modest (20-fold) rabbit A3 receptor selectivity of CP-608,039 precludes demonstration of A3-mediated cardioprotection in rabbit models, we identified another member of this class, (2S,3S,4R,5R)-3-amino-5-[6-(2,5-dichlorobenzylamino)purin-9-yl]-4-hydroxytetrahydrofuran-2-carboxylic acid methylamide (CP-532,903), which both retained human A3 receptor selectivity (210-fold; human A3/human A1 Ki: 23/4,800 nM) and had improved rabbit A3 receptor selectivity (90-fold; rabbit A3/rabbit A1 Ki: 23/2,000 nM).

3'-Aminoadenosine-5'-uronamides: discovery of the first highly selective agonist at the human adenosine A3 receptor.

Selective adenosine A(3) agonists have potential utility for the prevention of perioperative myocardial ischemic injury. Herein, we report on the discovery and synthesis of compound 7. This amino nucleoside agonist possesses unprecedented levels of selectivity for the human adenosine A(3) receptor.

Selective activation of adenosine A3 receptors with N6-(3-chlorobenzyl)-5'-N-methylcarboxamidoadenosine (CB-MECA) provides cardioprotection via KATP channel activation.

Objective: The aim of this study was to characterize the adenosine A3 receptor agonist, N6-(3-chlorobenzyl)-5'-N-methylcarboxamidoadenosine (CB-MECA), evaluate its ability to reduce myocardial ischemia/reperfusion injury and determine the role of KATP-channel activation in A3 receptor-mediated cardioprotection.

Methods: Binding affinities and adenylate cyclase inhibition were examined in CHO cells expressing rabbit recombinant adenosine A1 or A3 receptors. Infarct size (normalized for area-at-risk; % IA/AAR) was measured in buffer-perfused rabbit hearts exposed to 30-min regional ischemia and 120 min of reperfusion.

Relative importance of adenosine A1 and A3 receptors in mediating physiological or pharmacological protection from ischemic myocardial injury in the rabbit heart.

Although ischemic preconditioning (IP) in several species can be pharmacologically mimicked by selective adenosine A1 or A3 receptor agonists, it is currently unclear which receptor subtype (A1 and/or A3) is physiologically involved in mediating IP. To investigate this question, we determined (a) the affinity of adenosine for rabbit adenosine A1 and A3 receptors, and (b) the effects of selective rabbit A1 receptor blockade on IP and adenosine-mediated cardioprotection in a rabbit Langendorff model of myocardial ischemia-reperfusion injury. Adenosine was 19-fold selective for inhibition of N6-(4-amino-3-[125I]iodobenzyl)adenosine (125I-ABA) binding to recombinant rabbit A1 v rabbit A3 receptors (A1 Ki: 28 nm; A3 Ki 532 nm).

Expression of the rat adrenomedullin receptor or a putative human adrenomedullin receptor does not correlate with adrenomedullin binding or functional response.

There has been considerable difficulty in defining distinct adrenomedullin (AM) binding sites and function in vivo. However, a rat adrenomedullin receptor (rAMR) and a putative human adrenomedullin receptor (hAMR) have recently been reported. We attempted to confirm and extend the pharmacological characterization of these cloned receptors.

Antimycins, inhibitors of ATP-citrate lyase, from a Streptomyces sp.

A related group of compounds belonging to the antimycin class of antibiotics was found in culture broth produced by a Streptomyces species. The group includes known antimycins A1, A2, A3 and A4, and new antimycins A7 and A8. These compounds inhibit ATP-citrate lyase with Ki values of 4 to 60 microM against the substrate magnesium citrate.

Cloning, expression and pharmacological characterization of rabbit adenosine A1 and A3 receptors.

The role of adenosine A1 and A3 receptors in mediating cardioprotection has been studied predominantly in rabbits, yet the pharmacological characteristics of rabbit adenosine A1 and A3 receptor subtypes are unknown. Thus, the rabbit adenosine A3 receptor was cloned and expressed, and its pharmacology was compared with that of cloned adenosine A1 receptors. Stable transfection of rabbit A1 or A3 cDNAs in Chinese hamster ovary-K1 cells resulted in high levels of expression of each of the receptors, as demonstrated by high-affinity binding of the A1/A3 adenosine receptor agonist N6-(4-amino-3-[125I]iodobenzyl)adenosine (125I-ABA).

AMPA (amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptors in human brain tissues.

AMPA receptors may play an important role in acute and chronic neurodegenerative diseases. An assay for the specific binding of [3H]-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) to receptors in membranes from post-mortem human brain is described, which can be used in screening for selective AMPA receptor antagonists. Membranes were prepared from frozen human adult hippocampus and whole fetal brain tissues.

WIN 64821, a novel neurokinin antagonist produced by an Aspergillus sp. II. Biological activity.

WIN 64821, a secondary metabolite produced by Aspergillus sp. (ATCC 74177) was found to inhibit radiolabeled substance P (SP) binding in a variety of tissues, including those of human origin. This compound inhibited, in a competitive manner, the binding of SP with Ki values ranging from 0.

Role of protein sulfation in vasodilation induced by minoxidil sulfate, a K+ channel opener.

Evidence from contractile, radioisotope ion flux and electrophysiological studies suggest that minoxidil sulfate (MNXS) acts as a K+ channel opener in vascular smooth muscle. This study was designed to examine possible biochemical mechanisms by which MNXS exerts such an effect. Experiments performed in the isolated rabbit mesenteric artery (RMA) showed that MNXS, 5 microM, but not the parent compound minoxidil, was a potent vasodilator.

Characterization of K+ channel-dependent as well as -independent components of pinacidil-induced vasodilation.

The mechanisms of pinacidil-induced direct vasodilation were studied in vitro in RMA and RAO. In RMA, pinacidil produced dose-dependent relaxations of norepinephrine (5 microM)-induced contractions with an IC50 of 0.2 microM.

A sensitive in vitro functional assay to detect K(+)-channel-dependent vasodilators.

This study describes a sensitive in vitro relaxation assay using isolated rabbit mesenteric artery to detect the activity of a vasodilator as a K(+)-channel activator. Thus, comparison of several known K(+)-channel activators was made with other vasodilators known to work via various cellular mechanisms. The vasodilators used were minoxidil sulfate (MNXS; 5 microM), BRL-34915 (cromakalim, 0.