piperidines and carbetapentane

We investigated the effects of sigma receptor ligands on neuronal death induced by chemical ischemia using primary cultures of rat cerebral cortical neurons. The induction of chemical ischemia by sodium azide and 2-deoxy-D-glucose led to delayed neuronal death in a time- and concentration-dependent manner, as determined by trypan blue exclusion. The neurotoxicity was inhibited by N-methyl-D-aspartate (NMDA) receptor antagonists, indicating the involvement of glutamate. The sigma receptor ligands (+)-N-allylnormetazocine ((+)-SKF10,047) and haloperidol, but not carbetapentane and R(+)-3-(3-hydroxyphenyl)-N-propylpiperidine ((+)-3-PPP), prevented chemical ischemia-induced neurotoxicity in a concentration-dependent manner. The protective effects of (+)-SKF10,047 and haloperidol were not affected by the sigma receptor antagonists. (+)-SKF10,047 and haloperidol, but not carbetapentane and (+)-3PPP, inhibited the glutamate-induced increase in intracellular Ca(2+), and the inhibitory effects were not attenuated by sigma receptor antagonists. These results suggest that direct interaction with NMDA receptors but not sigma receptors is crucial to the neuroprotective effects of sigma receptor ligands with affinity for NMDA receptors.

Topics: 2-Amino-5-phosphonovalerate; Animals; Calcium; Cell Hypoxia; Cell Survival; Cells, Cultured; Cerebral Cortex; Cyclopentanes; Deoxyglucose; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Fetus; Glucose; Glutamates; Haloperidol; Neurons; Phenazocine; Piperidines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Receptors, sigma; Sodium Azide

The role of the putative sigma receptor in mediating neuroprotection against glutamate-induced neuronal injury was examined in mature cultured rat cortical neurons. With the exception of the selective sigma 1 ligand (+)-3-PPP, all of the sigma ligands tested were neuroprotective, preventing glutamate-induced morphological changes and increases in LDH release. Their rank order of neuroprotective potency (and EC50 values) was as follows: (+)-SKF 10,047 (0.81 microM) > (+)- cyclazocine (2.3 microM) > dextromethorphan (3.1 microM) = haloperidol (3.7 microM) > (+)-pentazocine (8.5 microM) > DTG (42.7 microM) = carbetapentane (46.3 microM). When corrected for relative sigma versus PCP binding affinity, it appears that a positive correlation exists between neuroprotective potency and sigma 1 site affinity. However, there does not appear to be a significant correlation between neuroprotective potency and the sigma 2 site. Critically, none of the sigma ligands were neurotoxic when tested alone at concentrations at least 5-30 times their respective neuroprotective EC50 values. Results from preliminary experiments with the selective sigma 1 ligand (+)-pentazocine indicated that sigma-mediated neuroprotection may involve the buffering of glutamate-induced calcium flux. Collectively, the results of these in vitro experiments demonstrate that sigma ligands are neuroprotective and therefore deserve further exploration as potential therapeutic agents in in vivo models of CNS injury and neurodegenerative disorders.

Topics: Animals; Calcium; Cells, Cultured; Cyclazocine; Cyclopentanes; Dextromethorphan; Glutamic Acid; Guanidines; Haloperidol; L-Lactate Dehydrogenase; Neurons; Neuroprotective Agents; Pentazocine; Phenazocine; Piperidines; Rats; Receptors, sigma