N-Arylalkylpiperidines as High-Affinity Sigma-1 and Sigma-2 Receptor Ligands: Phenylpropylamines as Potential Leads for Selective Sigma-2 Agents

Maeda, Dean Y.; Williams, Wanda; Kim, Wes E.; Thatcher, Linn N.; Bowen, Wayne D.; Coop, Andrew

doi:10.1016/s0960-894x(01)00788-0

Cited by 31 publications

(36 citation statements)

References 24 publications

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“…The competition binding studies confirmed that UMB24 and (±)-SM 21 have preferential affinity for σ 2 receptors, as compared to σ 1 receptors (Mach et al, 1999;Maeda et al, 2002). (±)-SM 21 exhibited nearly 10-fold preferential affinity for σ 2 receptors, as compared to σ 1 receptors, while UMB24 exhibited only about a 2-fold preference.…”

Section: Radioligand Binding Assaysmentioning

confidence: 58%

“…(1-(2-phenethyl)-4-(2-pyridyl)-piperazine) was synthesized as described previously (Maeda et al, 2002). (±)-SM 21 maleate was purchased from Tocris (Ballwin, MO).…”

Section: Umb24mentioning

confidence: 99%

“…Although reports of σ 2 ligands abound in the literature (Bertha et al, 1995;Bowen et al, 1995a,b;Kassiou et al, 2005;Mach et al, 1995;Maeda et al, 2002;Maier and Wunsch, 2002;Perregaard et al, 1995;Vangveravong et al, 2006), the primary criterion for these claims appears to be reasonable affinity for this receptor subtype relative to σ 1 , with little consideration for selectivity as compared to non-σ binding sites. In addition, the few σ 2 compounds that have been tested in functional studies appear to act as agonists (Bowen et al, 1995a,b;Crawford et al, 2002;Vilner and Bowen, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…Among piperazine analogs of AC927 which were subsequently developed, UMB24 (1-(2-phenethyl)-4-(2-pyridyl)-piperazine) has been reported as a potential lead for the development of selective σ 2 receptor agents (Maeda et al, 2002). Due to its structural relationship to AC927, it was conceivable that UMB24 also possessed antagonist actions at σ 2 receptors.…”

Section: Introductionmentioning

confidence: 99%

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Effects of UMB24 and (±)-SM 21, putative σ2-preferring antagonists, on behavioral toxic and stimulant effects of cocaine in mice

Matsumoto

Pouw

Mack

et al. 2007

Pharmacology Biochemistry and Behavior

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Earlier studies have demonstrated that antagonism of σ 1 receptors attenuates the convulsive, lethal, locomotor stimulatory and rewarding actions of cocaine in mice. In contrast, the contribution of σ 2 receptors is unclear because experimental tools to selectively target this subtype are unavailable. To begin addressing this need, we characterized UMB24 (1-(2-phenethyl)-4-(2-pyridyl)-piperazine) and (±)-SM 21 (3α-tropanyl-2-(4-chorophenoxy)butyrate) in receptor binding and behavioral studies. Receptor binding studies confirmed that UMB24 and (±)-SM 21 display preferential affinity for σ 2 over σ 1 receptors. In behavioral studies, pretreatment of Swiss Webster mice with UMB24 or (±)-SM 21 significantly attenuated cocaine-induced convulsions and locomotor activity, but not lethality. When administered alone, (±)-SM 21 produced no significant effects compared to control injections of saline, but UMB24 had locomotor depressant actions. Together, the data suggest that σ 2 receptor antagonists have the potential to attenuate some of the behavioral effects of cocaine, and further development of more selective, high affinity ligands are warranted.

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Section: Radioligand Binding Assaysmentioning

confidence: 58%

“…(1-(2-phenethyl)-4-(2-pyridyl)-piperazine) was synthesized as described previously (Maeda et al, 2002). (±)-SM 21 maleate was purchased from Tocris (Ballwin, MO).…”

Section: Umb24mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of UMB24 and (±)-SM 21, putative σ2-preferring antagonists, on behavioral toxic and stimulant effects of cocaine in mice

Matsumoto

Pouw

Mack

et al. 2007

Pharmacology Biochemistry and Behavior

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“…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%

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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N-Arylalkylpiperidines as High-Affinity Sigma-1 and Sigma-2 Receptor Ligands: Phenylpropylamines as Potential Leads for Selective Sigma-2 Agents

Cited by 31 publications

References 24 publications

Effects of UMB24 and (±)-SM 21, putative σ2-preferring antagonists, on behavioral toxic and stimulant effects of cocaine in mice

Effects of UMB24 and (±)-SM 21, putative σ2-preferring antagonists, on behavioral toxic and stimulant effects of cocaine in mice

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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