Effects of SKF83959 on the excitability of hippocampal CA1 pyramidal neurons: a modeling study

Abstract

Aim: 3-Methyl-6-chloro-7,8-hydroxy-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF83959) have been shown to affect several types of voltage-dependent channels in hippocampal pyramidal neurons. The aim of this study was to determine how modulation of a individual type of the channels by SKF83959 contributes to the overall excitability of CA1 pyramidal neurons during either direct current injections or synaptic activation. Methods: Rat hippocampal slices were prepared. The kinetics of voltage-dependent Na + channels and neuronal excitability and depolarization block in CA1 pyramidal neurons were examined using whole-cell recording. A realistic mathematical model of hippocampal CA1 pyramidal neuron was used to simulate the effects of SKF83959 on neuronal excitability. Results: SKF83959 (50 μmol/L) shifted the inactivation curve of Na + current by 10.3 mV but had no effect on the activation curve in CA1 pyramidal neurons. The effects of SKF83959 on passive membrane properties, including a decreased input resistance and depolarized resting potential, predicted by our simulations were in agreement with the experimental data. The simulations showed that decreased excitability of the soma by SKF83959 (examined with current injection at the soma) was only observed when the membrane potential was compensated to the control levels, whereas the decreased dendritic excitability (examined with current injection at the dendrite) was found even without membrane potential compensation, which led to a decreased number of action potentials initiated at the soma. Moreover, SKF83959 significantly facilitated depolarization block in CA1 pyramidal neurons. SKF83959 decreased EPSP temporal summation and, of physiologically greater relevance, the synaptic-driven firing frequency. Conclusion: SKF83959 decreased the excitability of CA1 pyramidal neurons even though the drug caused the membrane potential depolarization. The results may reveal a partial mechanism for the drug's anti-Parkinsonian effects and may also suggest that SKF83959 has a potential antiepileptic effect.

Recent Advances in the Realm of Allosteric Modulators for Opioid Receptors for Future Therapeutics

“…75 Unlike E1R, which is selective for the sigma-1 receptor, SKF83959 has inherent D 1 dopamine receptor affinity among other activities. 76–80 In an effort to ablate these off-target interactions, a series of modifications were performed, bringing to fruition SOMCL668, which exhibited no appreciable activity at the dopamine 1(D 1 ), D 2 , D 3 , 5-hydroxytryptamine 1A (HT), or 5-HT 2A receptors. 81,82 …”

“…SKF83959 afforded improved binding and an increased PAM effect relative to that of phenytoin, a classic sigma-1 receptor PAM. , In an additional study, it was demonstrated that SFK83959 enhanced the binding activity of dehydroepiandrosterone, an endogenous agonist for the sigma-1 receptor . Unlike E1R, which is selective for the sigma-1 receptor, SKF83959 has inherent D 1 dopamine receptor affinity among other activities. − In an effort to ablate these off-target interactions, a series of modifications were performed, bringing to fruition SOMCL668, which exhibited no appreciable activity at the dopamine 1­(D 1 ), D 2 , D 3 , 5-hydroxytryptamine 1A (HT), or 5-HT 2A receptors. , …”

Allosteric Modulation of Sigma‐1 Receptors Elicits Rapid Antidepressant Activity

“…Recently, two novel sigma-1 receptor allosteric modulators, SKF83959 and ER1, have been identified in our laboratory [14] and by another group [15]. Although SKF83959 is a very potent sigma-1 receptor allosteric modulator, the selectivity is relatively weak because SKF83959 has D 1 dopamine receptor affinity and other activities [16][17][18][19][20]. To eliminate the potential effects of SKF83959 on the D 1 and serotonin receptors, we conducted a series of structural modifications and developed the new compound 3-methyl-phenyl-2, 3, 4, 5-tetrahydro-1H-benzo[d]azepin-7-ol (SOMCL-668), referred to as SOMCL-668 (Figure S1).…”