Is a Nitrogen Atom an Important Pharmacophoric Element in Sigma Ligand Binding?

Ablordeppey, Seth Y.; Fischer, James B.; Glennon, Richard A.

doi:10.1016/s0968-0896(00)00148-6

Cited by 67 publications

(86 citation statements)

References 23 publications

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“…CoMFA models were derived for activity at both DAT and σ 1 receptors. The comparison of the distances for a template molecule with previously proposed σ receptor models 22,24 showed significant compatibility, suggesting that these rimcazole analogues likely bind using the described pharmacophoric features. The σ 1 receptor model showed common features with the DAT model, providing sites where ligands could be modified to develop and optimize the activity at both targets.…”

Section: Discussionmentioning

confidence: 79%

Dual Probes for the Dopamine Transporter and σ₁ Receptors: Novel Piperazinyl Alkyl-bis(4‘-fluorophenyl)amine Analogues as Potential Cocaine-Abuse Therapeutic Agents

et al. 2003

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Both dopamine uptake inhibitors and σ 1 receptor antagonists have been implicated as potential pharmacotherapeutics for the treatment of cocaine abuse. While the dopamine uptake inhibitors may share with cocaine neurochemical mechanisms underlying reinforcing properties, σ 1 antagonists have been shown to attenuate some behavioral actions and toxic side effects associated with cocaine overdose. Rimcazole, a σ 1 receptor antagonist that binds to the DAT (K i ) 224 nM), is not behaviorally cocaine-like and attenuates some of the behavioral actions of cocaine. To determine the roles of both DAT and σ 1 receptors in the behavioral actions of rimcazole, a series of analogues was synthesized. Initial studies identified two analogues (1 and 4) that showed high to moderate affinities for both DAT and σ 1 receptors and failed to show cocaine-like discriminative stimulus (DS) effects. A second series of bis(4′-fluorophenyl)-amine analogues have now been prepared in which the most potent DAT compound, 19 (K i ) 8.5 nM), was selective over serotonin transporter (SERT/DAT ) 94), norepinephrine transporter (NET/DAT ) 63), and σ 1 receptor binding (σ 1 /DAT ) 44). In addition, two other analogues 10 and 17 showed superior selectivity for DAT over SERT (170-and 140-fold, respectively) and DAT over NET (219-and 190-fold, respectively) but were essentially equipotent at DAT and σ 1 receptors (10; K i ) 77 and 124 nM, respectively, 17; K i ) 28 and 13 nM, respectively). CoMFA studies at both DAT and σ 1 receptors were performed to examine structural requirements for optimal binding at these two targets as well as to assess differences between them. Behavioral evaluation of analogues with varying affinities for both DAT and σ 1 receptors may provide a novel approach toward designing medications for cocaine abuse.

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Section: Discussionmentioning

confidence: 79%

Dual Probes for the Dopamine Transporter and σ₁ Receptors: Novel Piperazinyl Alkyl-bis(4‘-fluorophenyl)amine Analogues as Potential Cocaine-Abuse Therapeutic Agents

et al. 2003

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“…Although we have previously shown that putative S1R ligands inhibit HCV infection, most of these compounds selectively and efficiently inhibit viral entry (35), a process that is not altered by S1R downregulation (Fig. 7), probably due to their lysosomotropic properties as weak amines, a structural feature that appears to be important for synthetic ligands to bind S1R (72). Thus, in view of the evidence presented in this study and the reported ability of putative S1R ligands to modulate cellular processes in an S1R-independent manner (73), we suspect that the antiviral activity of the putative S1R ligands that prompted this study is not mediated by S1R.…”

Section: Discussionmentioning

confidence: 91%

Sigma-1 Receptor Regulates Early Steps of Viral RNA Replication at the Onset of Hepatitis C Virus Infection

Friesland

Mingorance

Chung

et al. 2013

J Virol

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bHepatitis C virus (HCV) genome replication is thought to occur in a membranous cellular compartment derived from the endoplasmic reticulum (ER). The molecular mechanisms by which these membrane-associated replication complexes are formed during HCV infection are only starting to be unraveled, and both viral and cellular factors contribute to their formation. In this study, we describe the discovery of nonopioid sigma-1 receptor (S1R) as a cellular factor that mediates the early steps of viral RNA replication. S1R is a cholesterol-binding protein that resides in lipid-rich areas of the ER and in mitochondrion-associated ER membranes (MAMs). Several functions have been ascribed to this ER-resident chaperone, many of which are related to Ca 2؉ signaling at the MAMs and lipid storage and trafficking. Downregulation of S1R expression by RNA interference (RNAi) in Huh-7 cells leads to a proportional decrease in susceptibility to HCV infection, as shown by reduced HCV RNA accumulation and intra-and extracellular infectivity in single-cycle infection experiments. Similar RNAi studies in persistently infected cells indicate that S1R expression is not rate limiting for persistent HCV RNA replication, as marked reduction in S1R in these cells does not lead to any decrease in HCV RNA or viral protein expression. However, subgenomic replicon transfection experiments indicate that S1R expression is rate limiting for HCV RNA replication without impairing primary translation. Overall, our data indicate that the initial steps of HCV infection are regulated by S1R, a key component of MAMs, suggesting that these structures could serve as platforms for initial RNA replication during HCV infection. It is estimated that 170 million humans are chronically infected with hepatitis C virus (HCV). Chronic HCV infection is associated with persistent liver inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma (1). Recently, combination therapy, including pegylated alpha 2a interferon (IFN-␣2a), ribavirin, and specific HCV protease inhibitors, has been approved for the treatment of HCV-infected patients, with high cure rates compared with pegylated IFN-␣2a and ribavirin alone, the previous standard of care (2, 3). However, adverse effects and cost considerations limit the implementation of these new treatment regimens.HCV is an enveloped RNA virus with a single 9.6-kb positivestrand RNA genome that encodes a single open reading frame of approximately 3,000 amino acids flanked by 5= and 3= untranslated regions (UTR) that regulate translation and replication of the viral genome. The 5= UTR contains an internal ribosomal entry site (4) that cooperates with the 3= UTR regions for efficient viral polyprotein translation and RNA replication. Individual viral proteins are produced as a result of the sequential proteolysis of the HCV polyprotein by cellular and viral proteases, which produce structural proteins (core, E1, and E2) that are major components of the viral particles and p7 and NS2, which mediate infectious-particle assembly in...

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“…as with piperazine derivatives). To some extent, binding character is not unlike that proposed for σ 1 ligands (Gilligan et al, 1992;Glennon et al, 1994;Ablordeppey et al, 2000); indeed, most compounds bind at both σ receptor subtypes with, frequently, <10-fold selectivity. On the other hand, compounds such as 101-103 suggest that real differences exist -subtle though they may be.…”

Section: Binding Character Of σ σ σ σ σ 2 Receptor Ligandsmentioning

confidence: 94%

“…That is, this review is based on ligands we reported in a series of articles published over the past 15 years (e.g. Ablordeppey et al, 1991;Ablordeppey et al, 1992a;Ablordeppey et al, 1992b;Ablordeppey et al, 1993;Ablordeppey et al, 1998;Ablordeppey et al, 2000;Ablordeppey et al, 2002;El-Ashmawy et al, 1992;Glennon et al, 1991a;Glennon et al, 1991b;Glennon et al, 1991c;Glennon et al, 1994;Glennon, 2000;Glennon, and Fischer 2000;Glennon et al, 2004); these papers can be consulted for the synthesis and physicochemical properties of most of the compounds described here. Sigma-2 receptor binding data were obtained using guinea pig brain homogenates and the nonselective [ One of the first sigma ligands we reported was R(-)PPAP (5R); the structure might be viewed as an N-phenylpropyl derivative of a ring-opened benzomorphan.…”

Section: Binding Character Of σ σ σ σ σ 2 Receptor Ligandsmentioning

confidence: 99%

“…To account for this we suggested that multiple modes of binding are possible. That is, we proposed two different modes of binding for piperidine derivatives, and four possible modes of binding for piperazine derivatives (Ablordeppey et al, 2000), depending upon the presence of one or two basic nitrogen atoms, the length of the alkyl chain, and substituents that might be present in aryl portions of the chain. A similar argument can be made here for the binding of these ligands at σ 2 receptors (Figure 1).…”

Section: Binding Character Of σ σ σ σ σ 2 Receptor Ligandsmentioning

confidence: 99%

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<![CDATA[Binding characteristics of sigma2 receptor ligands]]>

Glennon¹

2005

Rev. Bras. Cienc. Farm.

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Is a Nitrogen Atom an Important Pharmacophoric Element in Sigma Ligand Binding?

Cited by 67 publications

References 23 publications

Dual Probes for the Dopamine Transporter and σ₁ Receptors: Novel Piperazinyl Alkyl-bis(4‘-fluorophenyl)amine Analogues as Potential Cocaine-Abuse Therapeutic Agents

Dual Probes for the Dopamine Transporter and σ₁ Receptors: Novel Piperazinyl Alkyl-bis(4‘-fluorophenyl)amine Analogues as Potential Cocaine-Abuse Therapeutic Agents

Sigma-1 Receptor Regulates Early Steps of Viral RNA Replication at the Onset of Hepatitis C Virus Infection

<![CDATA[Binding characteristics of sigma2 receptor ligands]]>

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Is a Nitrogen Atom an Important Pharmacophoric Element in Sigma Ligand Binding?

Cited by 67 publications

References 23 publications

Dual Probes for the Dopamine Transporter and σ1 Receptors: Novel Piperazinyl Alkyl-bis(4‘-fluorophenyl)amine Analogues as Potential Cocaine-Abuse Therapeutic Agents

Dual Probes for the Dopamine Transporter and σ1 Receptors: Novel Piperazinyl Alkyl-bis(4‘-fluorophenyl)amine Analogues as Potential Cocaine-Abuse Therapeutic Agents

Sigma-1 Receptor Regulates Early Steps of Viral RNA Replication at the Onset of Hepatitis C Virus Infection

<![CDATA[Binding characteristics of sigma2 receptor ligands]]>

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Dual Probes for the Dopamine Transporter and σ₁ Receptors: Novel Piperazinyl Alkyl-bis(4‘-fluorophenyl)amine Analogues as Potential Cocaine-Abuse Therapeutic Agents

Dual Probes for the Dopamine Transporter and σ₁ Receptors: Novel Piperazinyl Alkyl-bis(4‘-fluorophenyl)amine Analogues as Potential Cocaine-Abuse Therapeutic Agents