piperidines and tibalosin

1. Antagonists acting at the polyamine site of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor, including a number of heterocyclic aminoalcohols related to ifenprodil, were investigated to establish their functional interaction at the NMDA receptor and their neuroprotective profile. 2. In murine cultured neocortical neurones, NMDA (100 microM)-stimulated production of guanosine 3':5'-cyclic monophosphate (cyclic GMP) was blocked by N-1([thienyl]-cyclohexyl)-piperidine (1 microM) and by the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine (100 microM). Ifenprodil and structurally related heterocyclic aminoalcohols inhibited in a concentration-dependent manner the NMDA-stimulated, NO-dependent production of cyclic GMP; rank potency order was: ifenprodil > 2309 BT > tibalosine > threo-tibalosine > 840S. 3. All of the polyamine NMDA antagonists blocked NMDA (300 microM)-stimulated increases in intracellular calcium concentrations as measured by changes in the fluorescence of pre-loaded fluo-3-acetoxy methyl ester. Rank potency order was: ifenprodil > 2309 BT > 840S > tibalosine > threo-tibalosine. 4. In a series of experiments to evaluate the effectiveness of the polyamine NMDA antagonists as blockers of NMDA-induced cytotoxicity, all of the drugs were found to inhibit the leakage of lactate dehydrogenase after the exposure of the murine neocortical cultures to NMDA (100 microM, 5 h). Rank potency order was: 2309 BT > ifenprodil > tibalosine > threo-tibalosine > 840S. 5. These results provide direct evidence that polyamine NMDA antagonists produce a functional blockade of the NMDA receptor complex. The heterocyclic amino alcohols described herein, likeifenprodil, block NMDA-mediated elevation of intracellular NO and calcium, two key events in the excitotoxic cascade, and are cytoprotective.

Topics: Animals; Calcium; Cells, Cultured; Cyclic GMP; Dose-Response Relationship, Drug; Female; Mice; N-Methylaspartate; Neurons; Piperidines; Propanolamines; Receptors, N-Methyl-D-Aspartate

The interaction of a novel series of heterocyclic amino alcohols with the sigma receptor site was assessed using radioligand binding and computerized molecular modelling. All heterocyclic amino alcohols, like the structurally related ifenprodil, fully inhibited the specific binding of [3H]R(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ([3H]3-PPP) to rat cerebral cortical membranes. All compounds recognised two populations of binding sites labelled by [3H]3-PPP and the proportion of sites in the high affinity state was 60-80% of the total sites. Some of the heterocyclic amino alcohols also displayed similar affinity for alpha 1-adrenoceptors labelled by [3H]prazosin, where the pattern of inhibition appears to be stereospecific, unlike that seen with the binding of [3H]3-PPP. The amino alcohols had negligible affinity for sites labelled by the N-methyl-D-aspartate channel ligand, [3H]-(N-1-[thienyl]cyclohexyl)piperidine. Quantitative conformational analyses indicated that the heterocyclic amino alcohols and ifenprodil fitted well to a sigma receptor site model; low energy conformers could be superimposed like other potent sigma receptor ligands with confidence to the sigma receptor model. Our results define a new class of sigma receptor ligands and extend the understanding of the molecular requirements for drugs active at the sigma receptor.

Topics: Adrenergic alpha-Antagonists; Amino Alcohols; Animals; Binding, Competitive; Cerebral Cortex; Crystallization; Dopamine Agonists; Heterocyclic Compounds; In Vitro Techniques; Ligands; Models, Molecular; Molecular Conformation; Piperidines; Propanolamines; Rats; Receptors, Adrenergic, alpha-1; Receptors, sigma