Phenytoin differentially modulates the affinity of agonist and antagonist ligands for σ 1 receptors of guinea pig brain

We evaluated the effects of phenytoin (DPH) on the affinity for sigma‐1 (σ 1 ) receptors of agonist or antagonist σ 1 ligands in guinea pig brain. Heterologous competition experiments showed that DPH (250 μM and 1 mM) concentration‐dependently increased the affinity of the σ 1 agonists dextromethorphan, (+)‐SKF‐10,047, (+)‐3‐PPP, and PRE‐084. However, neither DPH 250 μM nor 1 mM increased (in fact, they slightly decreased) the affinity of the σ 1 receptor antagonists haloperidol, BD 1063, NE‐100, progesterone, and BD 1047. These findings suggest that allosteric modulation by DPH of the affinity of σ 1 receptor ligands depends on the agonist or antagonist characteristics of the ligand. Therefore, determining in vitro the differential modulation by DPH of σ 1 ligand affinity appears to constitute a procedure that can predict the pharmacological profile of different σ 1 ligands. Synapse 55:192–195, 2005. © 2005 Wiley‐Liss, Inc.