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Neuronal SignalingMembrane Transporter/Ion Channel-

Sibutramine hydrochloride monohydrate ??????????????????5-HT(serotonin) ??????????????????????????????????????? (SNRI)???Sibutramine ?????????????????? K+??????KV4.3???IC50??? 17.3 ??M???

Serotonin TransporterPotassium Channel

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生物活性

Description

Sibutramine hydrochloride monohydrate is a novel5-HT(serotonin) and noradrenaline reuptake inhibitor (SNRI).  TheIC50for Sibutramine block of voltage-gated K+channel (KV)4.3is 17.3 ??M.

IC50& Target

5-HT (serotonin) reuptake[1]

IC50: 17.3 ??M (KV4.3)[2]

In Vitro

Sibutramine is a novel 5-HT (serotonin) and noradrenaline reuptake inhibitor (SNRI). Sibutramine reduces the food intake of rodents and this effect is partially or completely reversed by pretreating with 5-HT or noradrenaline antagonists, indicating that both neurotransmitters are involved in sibutramine's hypophagic effect[1]. Sibutramine causes the concentration-dependent block of the KV1.3 and KV3.1 currents with IC50s of 3.7 and 32.7 ??M, respectively. The steady-state currents of KV1.3 and KV3.1 are decreased by Sibutramine in a concentration-dependent manner with IC50s of 3.7??0.7 (n=6) and 32.7??5.0 ??M (n=5), respectively[2].

In Vivo

Sibutramine (SIB) (5 mg/kg ip), which blocks the reuptake of both 5-hydroxytryptamine (5-HT) and noradrenaline (NA), also requires ARC pro-opiomelanocortin (POMC) neurons to achieve its appetitive effects in male and female mice. Sibutramine (5 mg/kg) suppresses 3-hour dark cycle food intake to a comparable extent in young adult and middle-aged male and female POMC-EGFP mice[3]. In normal Wistar rats, 3 mg/kg Sibutramine produces a marked (~30%) inhibition of food intake on the first day of dosing. Consistent with published data, the effects of Sibutramine on food intake diminished with time, although cumulative food intake over the 9-day study is significantly (P<0.001) lower in Sibutramine-treated (213.3??5.7 g) than in vehicle-treated (260.2??3.0 g) rats. Sibutramine also significantly reduces overall body weight gain (vehicle 30??2 g, Sibutramine 14??3 g; P<0.001)[4].

Clinical Trial

NCT01421706

Inje University

Healthy

July 2008

Phase 1

NCT01170364

New York State Psychiatric Institute-AstraZeneca

Obesity

February 2009

NCT00234832

Abbott

Obesity

January 2003

Phase 3

NCT00941382

Laboratorios Silanes S.A. de C.V.

Obesity

November 2008

Phase 3

NCT00433641

Mayo Clinic-National Institutes of Health (NIH)

Obesity

July 2006

Phase 4

NCT00234988

Abbott

Obesity

June 2004

Phase 4

NCT01184560

Gachon University Gil Medical Center

Obesity

February 2010

NCT01023139

Brooke Army Medical Center-Wilford Hall Medical Center

Obesity

April 2009

NCT00037752

University of Tennessee-National Heart, Lung, and Blood Institute (NHLBI)

Cardiovascular Diseases-Heart Diseases-Obesity

September 2002

NCT00914212

Merck Sharp & Dohme Corp.

Obesity

May 2009

Phase 1

NCT00729963

Laval University

Obstructive Sleep Apnea-Obesity-Hypertension

January 2004

Phase 4

NCT00261911

Abbott

Obesity

July 2000

Phase 3

NCT00330525

Mayo Clinic

Obesity-Overweight

January 2005

Phase 2

NCT00463112

Hippocration General Hospital

Obesity-Polycystic Ovary Syndrome

March 2004

Phase 4

NCT00677391

Abbott

Obesity

December 2002

Phase 3

NCT00645255

Abbott

Obesity-Weight Loss

September 1998

Phase 3

NCT00402584

Abbott

Binge Eating Disorder-Obesity

August 2000

Phase 3

NCT00679653

Abbott

Obesity-Hypertension

February 2002

Phase 3

NCT00537810

Yale University-National Institutes of Health (NIH)-National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Obesity-Binge Eating

September 2007

Phase 4

NCT01475019

Aristotle University Of Thessaloniki

Obesity-Polycystic Ovaries Syndrome

January 2004

Phase 4

NCT00402077

AstraZeneca

Overweight-Obesity

November 2006

Phase 2

NCT00212173

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Protocol #1:Behavioral Therapy + Placebo or Sibutramine-Protocol #2: Behavioral Therapy + Meal Replacement or Conventional Food

NCT00993421

Eli Lilly and Company

Obesity

October 2009

Phase 2

NCT01597609

GlaxoSmithKline

Obesity

May 22, 2008

Phase 1

NCT00537420

Nastech Pharmaceutical Company, Inc.

Obesity

October 2007

Phase 2

NCT00165685

Eisai Limited-Eisai Inc.

Obesity

July 2004

Phase 3

NCT00044187

Eli Lilly and Company

Schizophrenia-Psychotic Disorders-Bipolar Disorder

April 2001

Phase 4

NCT00134199

Pfizer

Obesity

March 2005

Phase 2-Phase 3

NCT01047657

University of Sao Paulo General Hospital-Fundação de Amparo à Pesquisa do Estado de São Paulo

Asthma-Obesity-Weight Loss

November 2009

Phase 3

NCT00829283

Yale University-National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Obesity-Binge Eating

November 2008

NCT00115063

Pennington Biomedical Research Center-Louisiana Office of Group Benefits

Obesity

July 2005

Phase 4

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References

[1].Heal DJ,  et al. Sibutramine: a novel anti-obesity drug. A review of the pharmacological evidence to differentiate it from d-amphetamine and d-fenfluramine. Int J Obes Relat Metab Disord. 1998 Aug;22 Suppl 1:S18-28; discussion S29.

[2].Kim SE,  et al. Open channel block of A-type, kv4.3, and delayed rectifier K+channels, KV1.3 and KV3.1, bySibutramine. J Pharmacol Exp Ther. 2007 May;321(2):753-62.

[3].Burke LK, et al. 5-HT obesity medication efficacy via POMC activation is maintained during aging. Endocrinology. 2014 Oct;155(10):3732-8.

[4].Turnbull AV,  et al. Selective antagonism of the NPY Y5 receptor does not have a major effect on feeding in rats. Diabetes. 2002 Aug;51(8):2441-9.