Binding properties of SA4503, a novel and selective σ1 receptor agonist

Matsuno, Kiyoshi; Nakazawa, Minako; Okamoto, Kazuyoshi; Kawashima, Yasunaru; Mita, Shiro

doi:10.1016/0014-2999(96)00201-4

Cited by 174 publications

(120 citation statements)

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“…This result may be explained by the difference of affinities for the PCP binding sites between (ϩ)-SKF10,047, SA4503, and (ϩ)-pentazocine. Indeed, (ϩ)-SKF10,047 has a higher affinity for PCP binding sites (de Costa and He 1994), and SA4503 and (ϩ)-pentazocine are more selective sigma 1 receptor ago-nists (de Costa and He 1994;Matsuno et al 1996). Thus, it is suggested that (ϩ)-SKF-10,047 at the dose ranges used, especially 3 mg/kg, had PCP-like effects, since (ϩ)-SKF-10,047 (3 mg/kg) itself showed a tendency to prolong finding latency, but not drinking latency, but other sigma 1 receptor agonists, SA4503 and (ϩ)-pentazocine, themselves did not show it.…”

Section: Discussionmentioning

confidence: 99%

Phencyclidine Impairs Latent Learning in Mice Interaction between Glutamatergic Systems and Sigma1 Receptors

Noda

Kamei

et al. 2001

Neuropsychopharmacology

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Section: Discussionmentioning

confidence: 99%

Phencyclidine Impairs Latent Learning in Mice Interaction between Glutamatergic Systems and Sigma1 Receptors

Noda

Kamei

et al. 2001

Neuropsychopharmacology

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“…Cutamesine (1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl) piperazine dihydrochloride, SA4503), 10 an orally available, central nervous system active, selective agonist of the Sig-1R, enhanced functional recovery after experimental stroke in rats when treatment commenced 48 hours after stroke and continued for 1 month, without affecting infarct size.…”

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confidence: 99%

Phase II Trial of the Sigma-1 Receptor Agonist Cutamesine (SA4503) for Recovery Enhancement After Acute Ischemic Stroke

Urfer

Moebius

Školoudík

et al. 2014

Stroke

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E nhancement of functional recovery during the subacute and chronic phases of stroke represents a major therapeutic goal because a significant proportion of patients have persisting neurological deficits, even with optimal acute care and conventional rehabilitation. Preclinical in vivo models suggest that a time-limited window of neuroplasticity opens after stroke.1 New therapeutic approaches that stimulate these repair mechanisms may be able to exploit this opportunity, and a range of these is currently under investigation, including small molecules that target specific processes, small molecules that have a general stimulatory effect that may aid rehabilitation, growth factors, cell therapies, and physical modulation of neuronal networks.2 The σ-1 receptor chaperone protein (Sig-1R) mediated functional recovery in a model of neuronal plasticity relevant to stroke.3 Sig-1Rs mainly reside in the endoplasmic reticulum and are enriched in the mitochondriaassociated endoplasmic reticulum membrane but can change their intracellular location in response to cellular stress. 4 The biochemical function of the Sig-1R is that of a molecular chaperone, stabilizing proteins in response to cellular stress 5 Background and Purpose-The σ-1 receptor (Sig-1R) agonist cutamesine (SA4503) enhanced functional recovery after experimental stroke with a treatment initiation window of 48 hours and chronic treatment for 28 days. We conducted a phase 2 clinical trial exploring the safety, tolerability, dose range, and functional effects of cutamesine in patients with ischemic stroke. Methods-Subjects were randomized between 48 and 72 hours after stroke to receive cutamesine 1 mg/d, 3 mg/d, or placebo for 28 days. Effects on safety and function were assessed at baseline, at end of treatment (day 28), and at end of followup (day 56). Results-In 60 patients, treatment with both cutamesine dosages was safe and well tolerated without significant differences in numbers of treatment emergent or serious adverse events. No significant effect was observed on the primary efficacy measure (change in National Institutes of Health Stroke Scale from baseline to day 56) or modified Rankin Scale and Barthel Index scores. Post hoc analysis of moderately and severely affected patients (baseline National Institutes of Health Stroke Scale, ≥7 and ≥10) showed greater National Institutes of Health Stroke Scale improvements in the 3 mg/d cutamesine group when compared with placebo (P=0.034 and P=0.038, respectively). A trend toward a higher proportion being able to complete a 10m timed walk was observed for cutamesine-treated subjects. Conclusions-Cutamesine was safe and well tolerated at both dosage levels. Although no significant effects on functional end points were seen in the population as a whole, greater improvement in National Institutes of Health Stroke Scale scores among patients with greater pretreatment deficits seen in post hoc analysis warrants further investigation. Additional studies should focus on the patient population with moderate-to-severe...

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“…30,31) The binding affinity of SA4503 to sigma receptors indicates over 100 times higher than that of other receptors. Therefore, SA4503 has a potential to become lead compound of useful radiopharmaceutical for sigma receptors studies in the brain.…”

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confidence: 99%

“…30,31) It is also known that allyl iodides are more stable than alkyl iodides. 37,38) Thus, iodinated analogue of SA4503 were designed on the basis of the structure activity relationships to sigma receptors and in vivo stability.…”

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confidence: 99%

Synthesis and in Vitro Evaluation of Iodinated Derivatives of Piperazine as a New Ligand for Sigma Receptor Imaging by Single Photon Emission Computed Tomography

Hirata

Mori

Soga

et al. 2006

CHEMICAL & PHARMACEUTICAL BULLETIN

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Binding properties of SA4503, a novel and selective σ1 receptor agonist

Cited by 174 publications

References 58 publications

Phencyclidine Impairs Latent Learning in Mice Interaction between Glutamatergic Systems and Sigma1 Receptors

Phencyclidine Impairs Latent Learning in Mice Interaction between Glutamatergic Systems and Sigma1 Receptors

Phase II Trial of the Sigma-1 Receptor Agonist Cutamesine (SA4503) for Recovery Enhancement After Acute Ischemic Stroke

Synthesis and in Vitro Evaluation of Iodinated Derivatives of Piperazine as a New Ligand for Sigma Receptor Imaging by Single Photon Emission Computed Tomography

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