High Affinity For Sigma-1 Receptor Research Articles

Sertraline inhibits nerve growth factor-induced neurite outgrowth in PC12 cells via a mechanism involving the sigma-1 receptor

The selective serotonin reuptake inhibitors (SSRIs) fluvoxamine and sertraline show a high affinity for sigma-1 receptors. Fluvoxamine enhances nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells via a sigma-1 receptor-mediated mechanism, which suggests that neurogenesis may be involved in the antidepressant action of fluvoxamine. However, the effects of sertraline on neurite outgrowth remain unclear. Here, we report the effects of sertraline on NGF-induced neurite outgrowth in PC12 cells. At concentrations above 0.3 μM, sertraline inhibited neurite outgrowth induced by NGF (50 ng/mL) in PC12 cells in a concentration-dependent manner. At 0.3–3 μM, sertraline inhibited NGF-induced neurite outgrowth; however, had no effect on cell viability. This suggests that at these concentrations, sertraline inhibits NGF-induced neurite outgrowth without causing cell toxicity. Because sertraline has a high affinity for the sigma-1 receptor, we investigated whether this receptor is involved in sertraline's inhibitory effect on NGF-induced neurite outgrowth. The effect was reversed by both the sigma-1 receptor agonist PRE-084 and the sigma-1 receptor antagonist NE-100. These results suggest that sertraline inhibits NGF-induced neurite outgrowth in PC12 cells by acting as an inverse agonist of the sigma-1 receptor in this system.

Implementation of a proton pump inhibitor step-down program within a community-owned health system

Sigma-1 receptor is a target for tumor imaging. In a previous study, we synthesized a vesamicol analog, (+)-2-[4-(4-bromophenyl)piperidino]cyclohexanol [(+)-pBrV], with a high affinity for sigma-1 receptor, and synthesized radiobrominated (+)-pBrV. This radiobrominated (+)-pBrV showed high tumor uptake in tumor-bearing mice; however, radioactivity accumulation in normal tissues, such as the liver, was high. We assumed that the accumulation of (+)-pBrV in the non-target tissues was partially derived from its high lipophilicity; therefore, we synthesized and evaluated (+)-4-[1-(2-hydroxycyclohexyl)piperidine-4-yl]-2-bromophenol [(+)-BrV-OH], which is a more hydrophilic compound. Although we aimed to develop a PET tracer using 76Br, in these initial studies, we used 77Br because of its longer half-life.(+)-[77Br]BrV-OH was synthesized using the chloramine-T method with a radiochemical purity of 95%. Lipophilicity and affinity for sigma-1 receptor of (+)-[77Br]BrV-OH were determined, and biodistribution experiments were performed. We also performed an in vivo blocking study by co-injecting excess amounts of the sigma-1 receptor ligand, SA4503, into mice.The lipophilicity and affinity for sigma-1 receptor of (+)-[77Br]BrV-OH were lower than those of (+)-[77Br]pBrV. (+)-[77Br]BrV-OH also showed high tumor uptake in biodistribution experiments in DU-145 tumor-bearing mice,. Although (+)-[77Br]pBrV was retained in most tissues, (+)-[77Br]BrV-OH was cleared from these tissues. In blocking studies, the co-injection of SA4503 significantly decreased the tumor uptake of (+)-[77Br]BrV-OH.These results indicate that (+)-[76Br]BrV-OH has potential as a PET probe for sigma-1 receptor imaging.

Development of a novel radiobromine-labeled sigma-1 receptor imaging probe

IntroductionSigma-1 receptor is a target for tumor imaging. In a previous study, we synthesized a vesamicol analog, (+)-2-[4-(4-bromophenyl)piperidino]cyclohexanol [(+)-pBrV], with a high affinity for sigma-1 receptor, and synthesized radiobrominated (+)-pBrV. This radiobrominated (+)-pBrV showed high tumor uptake in tumor-bearing mice; however, radioactivity accumulation in normal tissues, such as the liver, was high. We assumed that the accumulation of (+)-pBrV in the non-target tissues was partially derived from its high lipophilicity; therefore, we synthesized and evaluated (+)-4-[1-(2-hydroxycyclohexyl)piperidine-4-yl]-2-bromophenol [(+)-BrV-OH], which is a more hydrophilic compound. Although we aimed to develop a PET tracer using 76Br, in these initial studies, we used 77Br because of its longer half-life. Methods(+)-[77Br]BrV-OH was synthesized using the chloramine-T method with a radiochemical purity of 95%. Lipophilicity and affinity for sigma-1 receptor of (+)-[77Br]BrV-OH were determined, and biodistribution experiments were performed. We also performed an in vivo blocking study by co-injecting excess amounts of the sigma-1 receptor ligand, SA4503, into mice. ResultsThe lipophilicity and affinity for sigma-1 receptor of (+)-[77Br]BrV-OH were lower than those of (+)-[77Br]pBrV. (+)-[77Br]BrV-OH also showed high tumor uptake in biodistribution experiments in DU-145 tumor-bearing mice,. Although (+)-[77Br]pBrV was retained in most tissues, (+)-[77Br]BrV-OH was cleared from these tissues. In blocking studies, the co-injection of SA4503 significantly decreased the tumor uptake of (+)-[77Br]BrV-OH. ConclusionThese results indicate that (+)-[76Br]BrV-OH has potential as a PET probe for sigma-1 receptor imaging.

Abstract 249: Sigma-1 Receptor Agonist Ameliorates Mitochondrial ATP Production and Apoptosis in Cardiac Myocytes

Objective: Selective serotonin reuptake inhibitors (SSRIs) are known to reduce post-myocardial infarction (MI)-induced morbidity and mortality. However, the molecular mechanism underlying SSRI-induced cardioprotection remains unclear. We previous reported that fluvoxamine with high affinity for sigma-1 receptor ameliorates cardiac hypertrophy and dysfunction via sigma-1 receptor stimulation. In non-cardiomyocytes, sigma-1 receptor interacts with IP 3 receptor (IP 3 R), which may promote Ca 2+ transport to mitochondria. We here investigated the role of sigma-1 receptor for sarcoplasmic reticulum (SR)-mitochondrial Ca 2+ signaling in neonatal rat ventricular cardiomyocytes. Methods: Cultured cardiomyocytes were treated with angiotensin II (Ang II) during 72 hr followed by fluvoxamine and/or NE-100 treatment during the last 24 hr. Then, we investigated intracellular localization of sigma-1 receptor and IP 3 R. We also measured phenylephrine (PE)-induced mitochondrial Ca 2+ and cytosolic Ca 2+ mobilization and ATP content in Ang II-treated cardiomyocytes with or without fluvoxamine treatments. Results: Ang II stimulation for 72 hr elicited cardiomyocyte hypertrophy, downregulation of sigma-1 receptor expression and declined PE-induced Ca 2+ mobilization into cytosol and mitochondria. Fluvoxamine treatments restored sigma-1 receptor expression and PE-induced Ca 2+ mobilization into mitochondria. Moreover, fluvoxamine treatment completely restored Ang II-induced apoptosis. We also confirmed in vivo that fluvoxamine treatment rescue transverse aortic constriction-induced cardiac dysfunction and the reduced ATP concentration. Conclusions: These results suggested that fluvoxamine rescue cardiomyocytes from AngII-induced cardiac myocyte apoptosis through enhancement of SR-mitochondria Ca 2+ transport and mitochondrial ATP production via sigma-1 receptor stimulation.

Influence of Trishomocubanes on Sigma Receptor Binding of N-(1-Benzylpiperidin- 4-yl)-4-[123I]iodobenzamide In Vivo in the Rat Brain

Three new trishomocubane analogues based on the 4-azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)] dodecane-3-ol skeleton have been synthesised and assessed for their affinities at both sigma-1 and sigma-2 receptors. The effect of various N-substitution on the polycyclic moiety was examined. All synthesised compounds displayed high affinity for sigma-1 receptors (9-10 nM) and good affinity for sigma-2 receptors (230-310 nM), suggesting that substitution at the nitrogen moiety of the trishomocubane is well tolerated and represents a platform for the development of improved higher affinity sigma receptor ligands. The interaction of these functionalised trishomocubanes on the binding of the known sigma receptor radioligand, 4-[123I]IBP, was evaluated in the rat brain. Although 4-[123I]IBP had been used for imaging sigma receptors in tumours, this is the first examination of sigma receptor binding in the rat brain and therefore the potential of 4-[123I]IBP for imaging the brain was also evaluated. In vivo specificity and selectivity of 4-[123I]IBP binding was examined by studying the effects of pre-administration of sigma receptor binding drugs (+)-pentazocine and unlabelled 4-IBP. This resulted in a blockade of only 42% of 4-[123I]IBP uptake in the brain indicating high degree of non-specific binding suggesting that it may not be suitable for imaging sigma receptors in the brain. The inhibition of 4-[123I]IBP uptake using the two of the three trishomocubanes displayed a consistent blockade of 48-30% in all brain structures. This demonstrates for the first time the ability of functionalised trishomocubanes to interact with sigma receptors in vivo.

1,4-Dibenzylpiperazines possess anticocaine activity

N,N-Dibenzylpiperazines have high affinity for sigma receptors, and we aimed to increase their anticocaine activity by introducing substituents known to enhance such activity in other sigma ligands. Ligands with high affinity for sigma-1 receptors resulted, but their activity in attenuating cocaine-induced convulsions did not correlate with sigma-1 binding affinity, and may be more closely related to their sigma-2 binding affinities.

Synthesis and quantitative structure-activity relationships of N-(1-benzylpiperidin-4-yl)phenylacetamides and related analogues as potent and selective sigma1 receptor ligands.

A series of N-(1-benzylpiperidin-4-yl)phenylacetamide derivatives was synthesized and evaluated for affinity at sigma1 and sigma2 receptors. Most of these compounds showed a high affinity for sigma1 receptors and a low to moderate affinity for sigma2 receptors. The unsubstituted compound N-(1-benzylpiperidin-4-yl)phenylacetamide, 1, displayed a high affinity and selectivity for sigma1 receptors (Ki values of 3.90 nM for sigma1 receptors and 240 nM for sigma2 receptors). The influence of substitutions on the phenylacetamide aromatic ring on binding at both the sigma1 and sigma2 receptor has been examined through Hansch-type quantitative structure-activity relationship (QSAR) studies. In general, all 3-substituted compounds, except for the OH group, had a higher affinity for both sigma1 and sigma2 receptors when compared with the corresponding 2- and 4-substituted analogues. The selectivity for sigma1 receptors displayed a trend of 3 > 2 approximately 4 for Cl, Br, F, NO2, and OMe substituted analogues. Halogen substitution on the aromatic ring generally increased the affinity for sigma2 receptors while maintaining a similar affinity for sigma1 receptors. Substitution with electron-donating groups, such as OH, OMe, or NH2, resulted in weak or negligible affinity for sigma2 receptors and a moderate affinity for sigma1 receptors. The 2-fluoro-substituted analogue, 11, exhibited the highest selectivity for sigma1 receptors among all compounds tested, with a Ki value of 3.56 nM for sigma1 receptors and 667 nM for sigma2 receptors. Compounds 1, 5, 9, 11, and 20 had no affinity for dopamine D2 (IC50 > 10 000 nM) and D3 (IC50 > 10 000 nM) receptors. The nanomolar binding affinity and high selectivity for sigma1 receptors suggest that these compounds may be developed as potential radiotracers for positron emission tomography or single photon emission computerized tomography imaging studies.