Bivalent ligands containing the oxymorphamine or naltrexamine pharmacophores connected to spacers of varying length were synthesized and evaluated for their selectivity at mu, kappa, and delta opioid receptors. The oxymorphamine bivalent ligands (1-8) behaved as mu agonists on the electrically stimulated guinea pig ileum longitudinal muscle preparation (GPI). The spacer that conferred peak agonist activity in these series contains a total of four glycyl units (n = 2). Binding studies with guinea pig brain membranes showed a qualitatively similar profile at mu receptors as a function of spacer length. Also, delta receptor selectivity increased as the spacer was lengthened. The naltrexamine bivalent ligands (9-13) effectively antagonized the mu receptor agonist morphine in the GPI at the same optimal spacer length (n = 2) as in the agonist series. However, the peak antagonism of ethylketazocine, a kappa receptor agonist, occurred with the bivalent ligand 9 containing the shortest spacer (n = 0), and it was found that 9 is the most selective kappa antagonist in the series. While receptor binding roughly parallels that of kappa antagonist activity in the GPI, no correlation between binding and antagonist activity was observed at mu opioid receptors. The possible significance of these results is discussed.
Prolonged exposure of cultured cortical neurons to the residue 25-35 fragment of beta-amyloid protein, in the presence of dizocilpine, an antagonist of the N-methyl-D-aspartate receptor, and of 6,7-dinitroquinoxaline-2,3-dione, an antagonist of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors, resulted in the expression of the proapoptotic protein Bax and neuronal death. Beta-amyloid protein(25-35)-induced neuronal death was substantially attenuated by the sigma1 receptor agonist 2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate. The neuroprotective action of 2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate was mimicked by the sigma1 ligand methyl (1S,2R)-2-[1-adamantyl(methyl)amino]methyl-1-phenylcyclopropanecarboxylate and was antagonized by the sigma1 receptor antagonist N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)-phenyl]-ethylamine monohydrochloride. These results suggest that sigma1 receptor agonists might function as neuroprotectant agents in Alzheimer's disease.
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