Novel analogs of the σ receptor ligand BD1008 attenuate cocaine-induced toxicity in mice

Matsumoto, Rae R.; Gilmore, Deborah L.; Pouw, Buddy; Bowen, Wayne D.; Williams, Wanda; KAUSAR, A. R.; Coop, Andrew

doi:10.1016/j.ejphar.2004.03.037

Cited by 34 publications

(45 citation statements)

References 29 publications

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“…Among those sites, the interaction with muscarinic receptors and sigma receptors were found to be related to the toxicity, seizure, or lethality of cocaine (Matsumoto et al, 2004;Ritz and George, 1993). Interaction with the sodium channels was also implicated to work against the reinforcing effect of local anesthetics (Wilcox et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

A Reduced Rate of In Vivo Dopamine Transporter Binding is Associated with Lower Relative Reinforcing Efficacy of Stimulants

Wee

2005

Neuropsychopharmacol

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A slow onset of action has been hypothesized to weaken the reinforcing effects of drugs. The present study evaluated this hypothesis with slow-onset cocaine analogs, WIN 35428, RTI 31, and RTI 51. When cocaine or a cocaine analog was made available to rhesus monkeys (n ¼ 4 or 5) for self-administration under a progressive-ratio (PR) schedule with a 1-h time-out between injections, all the drugs functioned as positive reinforcers. The maximum number of injections was in the order of cocaine4WIN 354284RTI 314RTI 51. In in vivo binding in rat striatum, equipotent doses of cocaine, WIN 35428, RTI 31, and RTI 51 were estimated to displace 25% of [ 3 H]WIN 35428 binding at the dopamine transporters (DAT), respectively, 5.8, 22.4, 30.8, and 44.1 min after the intravenous injection. Further, relative reinforcing efficacy was correlated with rate of DAT binding such that slower displacement of [ 3 H]WIN 35428 was associated with a weaker reinforcing effect. In in vitro binding in monkey brain tissue, the cocaine analogs had higher affinity for monoamine transporter sites, but similar affinity ratios of 5-HTT/DAT, compared to cocaine. Lastly, RTI 31 was shown to function as a positive reinforcer in drug-naïve rhesus monkeys under a fixed-ratio 1 schedule. Collectively, the data support the hypothesis that a slow onset at the DAT is associated with reduced reinforcing efficacy of DAT ligands. The data under both the PR and FR schedules, however, suggest that a slow onset at the DAT influence reinforcing effect only to a limited extent.

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Section: Discussionmentioning

confidence: 99%

A Reduced Rate of In Vivo Dopamine Transporter Binding is Associated with Lower Relative Reinforcing Efficacy of Stimulants

Wee

2005

Neuropsychopharmacol

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“…UMB23 was prepared as previously described (Maeda et al, 2002). UMB82 was synthesized following similar procedures to BD1008 and its analogs (de Costa et al, 1992;Matsumoto et al, 2004Matsumoto et al, , 2006. The compounds were converted to oxalate salts, and spectral analysis was consistent with their assigned structures.…”

Section: Drugs and Chemicalsmentioning

confidence: 99%

“…The affinities of the compounds for σ receptors and monoamine transporters were measured in rat brain homogenates using procedures previously described (Matsumoto et al, 2004). Competition binding assays were run for the two established σ receptor subtypes, σ-1 and σ-2.…”

Section: Radioligand Binding Assaysmentioning

confidence: 99%

“…Since antidepressant drugs interact with monoamine transporters, the affinities of the novel compounds for serotonin, norepinephrine, and dopamine transporters were also measured (Matsumoto et al, 2004). Briefly, serotonin transporters were assayed in 1.5 mg wet weight brainstem homogenates using 0.2 nM [ 3 H]paroxetine; non-specific binding was determined in the presence of 1.5 μM imipramine.…”

Section: Radioligand Binding Assaysmentioning

confidence: 99%

“…The novel compounds represent analogs of BD1008 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine) and AC927 (Nphenethylpiperidine oxalate), highly selective σ receptor ligands (de Costa et al, 1992;Maeda et al, 2002). From these two lead compounds, a number of selective σ receptor antagonists were developed (Maeda et al, 2002;Matsumoto et al, 2003Matsumoto et al, , 2004. However, initial functional characterizations suggested that the compounds, UMB23 (1-(3-phenylpropyl)piperidine oxalate) and UMB82 (2-(3,4-dichlorophenyl)-N-ethyl-N-(2-piperidin-1-ylethyl)ethanamine oxalate) acted as agonists, instead of antagonists, at σ receptors.…”

Section: Introductionmentioning

confidence: 99%

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Novel sigma (σ) receptor agonists produce antidepressant-like effects in mice

Wang

Mack

Coop

et al. 2007

European Neuropsychopharmacology

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Many antidepressant drugs interact with σ receptors and accumulating evidence suggests that these proteins mediate antidepressant-like effects in animals and humans. σ Receptors are localized in brain regions affected in depression, further strengthening the hypothesis that they represent logical drug development targets. In this study, two novel σ receptor agonists (UMB23, UMB82) were evaluated for antidepressant-like activity in mice. First, radioligand binding studies confirmed that the novel compounds had preferential affinity for σ receptors. Second, the forced swim test, a well established animal model for screening potential antidepressant drugs, showed that both compounds dose-dependently reduced immobility time. The σ receptor antagonist BD1047 attenuated the antidepressant-like effects of UMB23 and UMB82. Third, locomotor activity suggested that the effects of UMB23 and UMB82 in the forced swim test were not due to non-specific motor activating effects. Together, the data provide further evidence that σ receptor agonists represent a possible new class of antidepressant medication.

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A Medicinal‐Chemistry‐Guided Approach to Selective and Druglike Sigma 1 Ligands

et al. 2006

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Based on a medicinal-chemistry-guided approach, three novel series of druglike cycloalkyl-annelated pyrazoles were synthesized and display high affinity (pKi>8) for the sigma1 receptor. Structure-affinity relationships were established, and the different scaffolds were optimized with respect to sigma1 binding and selectivity versus the sigma2 receptor and the hERG channel, resulting in selective compounds that have Ki values (for sigma1) in the subnanomolar range. Selected compounds were screened for cytochrome P450 inhibition (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4), metabolic stability (rat and human liver microsomes), and cell-membrane permeability (Caco-2). They showed favorable in vitro ADME properties as well as favorable calculated druglike and experimental physicochemical properties. Furthermore, compounds 7 f and 17 a, for example, displayed high selectivity (affinity) for the sigma1 receptor against a wide range of other receptors (>60). With these valuable tool compounds in hand, we are further exploring the role of the sigma1 receptor in relevant animal models corresponding to such medicinal indications as drug abuse, pain, depression, anxiety, and psychosis.

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Novel analogs of the σ receptor ligand BD1008 attenuate cocaine-induced toxicity in mice

Cited by 34 publications

References 29 publications

A Reduced Rate of In Vivo Dopamine Transporter Binding is Associated with Lower Relative Reinforcing Efficacy of Stimulants

A Reduced Rate of In Vivo Dopamine Transporter Binding is Associated with Lower Relative Reinforcing Efficacy of Stimulants

Novel sigma (σ) receptor agonists produce antidepressant-like effects in mice

A Medicinal‐Chemistry‐Guided Approach to Selective and Druglike Sigma 1 Ligands

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