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[Are sigma receptors implicated in ischemic injury?]
A Klouz1, M H Loueslati, R Daghfous
1Département de pharmacologie et CNRS, faculté de Médecine Paris XII, 8 rue de Général Sarrail, 94010 Créteil, France.
Therapie
|January 25, 2002
Summary
S-16950, a novel sigma ligand, demonstrates high affinity for sigma-1 receptors, suggesting a link between sigma receptors and cellular protection. This trimetazidine derivative shows potential as an anti-ischaemic agent.
Area of Science:
- Neuropharmacology
- Receptor Binding Assays
- Drug Discovery
Context:
- Sigma receptors play roles in various physiological functions, but their specific roles and ligand selectivity remain unclear.
- Sigma-1 receptors are implicated in cellular protection, with ligands showing neuroprotective effects against ischemia.
- S-16950, a trimetazidine derivative, exhibits anti-ischemic properties and is structurally similar to the sigma receptor ligand SA4503.
Purpose:
- To characterize S-16950 as a sigma receptor ligand.
- To investigate the affinity and subtype selectivity of S-16950 for sigma receptors.
- To explore the potential mechanism of action of S-16950 as a sigma receptor agonist.
Summary:
- S-16950 demonstrated high affinity (IC50 = 7 nM) for sigma-1 receptors in rat brain membranes, comparable to potent ligands like haloperidol.
- The compound showed 170-fold higher affinity for sigma-1 receptors than for sigma-2 receptors.
- Functional assays suggest S-16950 may act as a sigma receptor agonist, indicated by its effects on [3H]pentazocine binding and potentiation of cocaine's convulsant effects.
Impact:
- Identifies S-16950 as a novel sigma ligand with high selectivity for the sigma-1 subtype.
- Provides evidence supporting the role of sigma receptors in cytoprotective mechanisms, particularly in ischemia-reperfusion.
- Suggests potential therapeutic applications for S-16950 in conditions involving cellular damage and ischemia.