ABSTRACT
The 5-HT3 receptor antagonist tropisetron (ICS 205-930) was found to be a potent and selective partial agonist at alpha7 nicotinic receptors. Two other 5-HT3 receptor antagonists, ondansetron and LY-278,584, were found to lack high affinity at the alpha7 nicotinic receptor. Quinuclidine analogues (1 and 2) of tropisetron were also found to be potent and selective partial agonists at alpha7 nicotinic receptors.
Subject(s)
Indoles/pharmacology , Nicotinic Agonists/pharmacology , Receptors, Nicotinic/drug effects , Serotonin Antagonists/pharmacology , Animals , Cell Membrane/chemistry , Hippocampus/ultrastructure , Inhibitory Concentration 50 , Intestine, Small/ultrastructure , Ligands , Membrane Potentials/drug effects , Mice , Oocytes/drug effects , Oocytes/physiology , Protein Binding , Rats , Receptors, Nicotinic/metabolism , Structure-Activity Relationship , Tropisetron , Xenopus , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
The synthesis of a series of novel 4,5-dihydro-4-oxo-2-(substituted amino)-3-furancarboxylic acids, salts, esters, and amides is described. The title compounds when tested in the mediator-induced dermal vascular permeability and active anaphylaxis assays in rats demonstrated moderate to potent antiallergic activity. The [2-trans-(4-methylphenyl)cyclopropyl]amino analogue 53 emerged as the most active derivative. Thus, when administered intraperitoneally to rats at a dose of 100 mg/kg, it inhibited the action of the mediators serotonin, histamine, and bradykinin by 100%. In the active anaphylaxis assay in rats, compound 30 suppressed the edema by 81% at a dose of 100 mg/kg, following intraperitoneal administration.
