Browsing by Author "Garcia, AG"
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- 1,6-C-H and 1,5-O-Si insertion reactions of alkylidenecarbene derivatives of monosaccharidesPublication . Van Nhien, AN; Leon, R; Postel, D; Carreiras, MC; Garcia, AG; Marco-Contelles, JA new protocol has been developed for the generation of alkylidenecarbene derivatives of monosaccharides based on the reaction of trimethylsilylazide and Bu2SnO with alpha-cyanomesylates derived from uloses. When this method is applied to conveniently functionalized carbohydrate derivatives it provides novel heterocyclic ring systems by the rare 1,6-C-H or 1,5-O-Si insertion reactions.
- Novel tacrine derivatives that block neuronal calcium channelsPublication . de los Rios, C; Marco, JL; Carreiras, MDC; Chinchon, PM; Garcia, AG; Villarroya, MA new series of tacrine (9-amino-1,2,3,4-tetrahydroacridine) derivatives were synthesized and their effects on Ca-45 (2+) entry into bovine adrenal chromaffin cells stimulated with dimethylphenylpiperazinium (DMPP) or K+, studied. At 3 PM, compound 1 did not affect Ca-45(2+) uptake evoked by DMPP. Compounds 14, 15 and 17 inhibited the effects of DMPP by 30%. Compounds 3, 9 and tacrine blocked the DMPP signal by about 50%. Compounds 5 and 12 were the most potent blockers of DMPP-stimulated (45)Ca2(+) entry (90%); the rest of the compounds inhibited the effects of DMPP by 70-80%. Compounds 1, 3, 4, 8, 10, If, 13, 16, 17 and tacrine inhibited Ca-45(2+) Uptake induced by K+ about 20%. Compounds 6. 14 and 15 inhibited the K+ effects by 10% or less. Compounds 7, 9, 12 and 18 blocked the K+ signal by 30% and, finally, compounds 2 and 5 inhibited the K+-induced Ca-45(2+) entry by 50%, None of the new compounds was as effective as diltiazem (IC50 0.03 muM) in causing relaxation of the rat aorta precontracted with 35 mM K+; the most potent was compound 7(IC50 = 0.3 muM). Compounds 5, 6, 8, 9, 10 and 13 had IC(50)s around 10 muM and compounds 3, 4, 11 and 12 around 20 muM. Blockade of Ca2+ entry through neuronal voltage-dependent Ca2+ channels, without concomitant blockade of vascular Ca2+ channels, suggests that some of these compounds might exhibit neuroprotectant effects but not undesirable hemodynamic effects. (C) 2002 Elsevier Science Ltd. All rights reserved.
- Synthesis and pharmacology of galantaminePublication . Marco-Contelles, J; Carreiras, MD; Rodriguez, C; Villarroya, M; Garcia, AG
- Synthesis, biological evaluation and molecular modelling of diversely functionalized heterocyclic derivatives as inhibitors of acetylcholinesterase/butyrylcholinesterase and modulators of Ca2+ channels and nicotinic receptorsPublication . Marco, JL; de los Rios, C; Garcia, AG; Villarroya, M; Carreiras, MC; Martins, C; Eleuterio, A; Morreale, A; Orozco, M; Luque, FJThe synthesis and the biological activity of compounds 5-40 as inhibitors of acetyleholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as modulators of voltage-dependent Ca2+ channels and nicotinic receptors, are described. These molecules are tacrine analogues, which have been prepared from polyfunctionalized 6-amino-5-cyano-4H-pyrans, 6-amino-5-cyano-pyridines and 5-amino-2-aryl-3-cyano-1,3-oxazoles via Friedlander reaction with selected cycloalkanones. These compounds are moderate acetylcholinesterase and butyrylcholinesterase inhibitors, the BuChE/AChE selectivity of the most active molecules ranges from 10.0 (compound 29) to 76.9 (compound 16). Interestingly, the 'oxazolo-tacrine' derivatives are devoid of any activity. All compounds showed an important inhibitory effect on the nicotinic acetylcholine receptor. Most of them also blocked L-type Ca2+ channels, and three of them, 64, 19 and 67, the non-L type of Ca2+ channels. Molecular modelling studies suggest that these compounds might bind at the peripheral binding site of AChE, which opens the possibility to design inhibitors able to bind at both, the catalytic and peripheral binding sites of the enzyme. (C) 2004 Elsevier Ltd. All rights reserved.