A discriminating pharmacophore model for noncompetitive metabotropic glutamate receptor antagonists of subtype 1 (mGluR1) was developed that facilitated the discovery of moderately active mGluR1 antagonists. One scaffold was selected for the design of several focused libraries where different substitution patterns were introduced. This approach facilitated the discovery of potent mGluR1 antagonists, as well as positive and negative mGluR5 modulators, because both receptor subtypes share similar binding pockets. For mGluR1 antagonists, a homology model of the mGlu1 receptor was established, and a putative binding mode within the receptor's transmembrane domain was visualized.
1 Recent results suggested that long-term treatment with a low dose of the organic nitrate pentaerythritol tetranitrate (PETN, 6 mg kg 71 per day) for 16 weeks slightly decreases aortic superoxide production in normal rabbits. We sought to determine if PETN can preserve endothelium dependent relaxation (EDR) in atherosclerotic rabbits. 2 Three groups of 9 ± 10 New Zealand White rabbits received a cholesterol chow (0.75%) for 16 weeks. One group (CHOL16) served as control and two groups were fed for another 16 weeks a cholesterol-chow without (CHOL32) or with 6 mg PETN kg 71 per day (PETN32). 3 Isolated aortic rings of CHOL16 showed a typical impairment of EDR with a maximal relaxation at 1 mM acetylcholine of 28+16%. In CHOL32-rings EDR was completely impaired. In striking contrast, EDR in PETN32 (24+15%) was similar to that of CHOL16 indicating a protective eect of PETN on endothelial function. Vascular superoxide production measured with the lucigenin method was not dierent between the groups. 4 Aortic lesion formation in PETN32 was smaller than in CHOL32 (P50.008). The onset of copper-induced LDL-oxidation (lag-time) after 16 weeks of cholesterol feeding (214+9 min) was reduced in CHOL32 (168+24 min, P=0.035) but not in PETN32 (220+21 min). This indicates prevention of increased LDL oxidation by PETN. 5 The halfmaximal eective vasodilator concentrations of PETN (in 7logM) were identical in CHOL16 (7.9+0.1), CHOL32 (7.6+0.2) and PETN32 (7.7+0.2). Similar results were obtained with S-nitroso-N-acetyl-D,L-penicillamine. 6 These data suggest that PETN can reduce the progression of lesion formation, endothelial dysfunction and of LDL-oxidation in established atherosclerosis.
These data suggest that eccentric ISMN can completely inhibit the increase of vascular bioavailability of superoxide and partially prevent intimal lesion formation and endothelial dysfunction in hypercholesterolemia.
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