ロベリン

ロベリン
IUPAC命名法による物質名
	IUPAC名 2-((2R,6S)-6-((S)-2-Hydroxy-2-phenylethyl)-1-methylpiperidin-2-yl)-1-phenylethanone;
臨床データ
Drugs.com	国別販売名(英語); International Drug Names
識別
CAS番号;	90-69-7
ATCvetコード	QV04CV01 (WHO)
PubChem	CID: 101616
ChemSpider	91814
UNII	D0P25S3P81
KEGG	D02364
ChEMBL	CHEMBL2103769
化学的データ
化学式	C22H27NO2
分子量	337.455
	SMILES O=C(C[C@@H]1N([C@@H](CCC1)C[C@@H](C2=CC=CC=C2)O)C)C3=CC=CC=C3;
	InChI InChI=1S/C22H27NO2/c1-23-19(15-21(24)17-9-4-2-5-10-17)13-8-14-20(23)16-22(25)18-11-6-3-7-12-18/h2-7,9-12,19-21,24H,8,13-16H2,1H3/t19-,20+,21-/m0/s1 ; Key:MXYUKLILVYORSK-HBMCJLEFSA-N ;
	テンプレートを表示

ロベリン（Lobeline）とはニコチン様構造を有するアルカロイドの一つであり、呼吸興奮薬として用いられる。末梢の化学受容器に作用して呼吸興奮作用を示す。ロベリア属の植物（ロベリアソウ（Lobelia inflata（英語版） ）、デビルズ・タバコ（Lobelia tupa（英語版） ）、カーディナル・フラワー（Lobelia cardinalis（英語版） ）、オオロベリアソウ（Lobelia siphilitica（英語版） ））やホシアザミ（Hippobroma longiflora（英語版） ）から発見された。ミゾカクシ（Lobelia chinensis ）にも含まれている。白い粉末状の物質で、水によく溶ける。

依存症治療

ロベリンは錠剤の形で禁煙補助剤として使われる^[1]^[2]^[3]。また、覚醒剤^[4]^[5]、コカイン^[6]等の薬物依存症やアルコール依存症^[7]の治療薬として使われる場合もある。

作用機序

ロベリンの作用部位は複数ある。単剤で用いるとVMAT2（英語版）に結合^[8]^[9]^[10]してドーパミンを弱く放出させるが、メタンフェタミンが作用している場合にはそのドーパミン分泌作用を減少させる^[11]^[12]。ドーパミンとセロトニンの再取り込みを阻害し^[13]、その結果細胞外ドメインのサブユニットに繋がるニコチン受容体^[14]に対して刺激・拮抗両効果を示す^[15]^[16]。μ-オピオイド受容体拮抗作用も持つ^[17]。

出典

^ Stead LF, Hughes JR; Hughes (2012). “Lobeline for smoking cessation”. Cochrane Database Syst Rev 2: CD000124. doi:10.1002/14651858.CD000124.pub2. PMID 22336780.
^ Marlow, S. P.; Stoller, J. K. (2003). “Smoking cessation”. Respiratory care 48 (12): 1238–54; discussion 1254–6. PMID 14651764.
^ Buchhalter, A. R.; Fant, R. V.; Henningfield, J. E. (2008). “Novel pharmacological approaches for treating tobacco dependence and withdrawal: Current status”. Drugs 68 (8): 1067–88. doi:10.2165/00003495-200868080-00005. PMID 18484799.
^ Neugebauer, N. M.; Harrod, S. B.; Stairs, D. J.; Crooks, P. A.; Dwoskin, L. P.; Bardo, M. T. (2007). “Lobelane decreases methamphetamine self-administration in rats”. European Journal of Pharmacology 571 (1): 33–8. doi:10.1016/j.ejphar.2007.06.003. PMC 2104779. PMID 17612524.
^ Eyerman, D. J.; Yamamoto, B. K. (2005). “Lobeline attenuates methamphetamine-induced changes in vesicular monoamine transporter 2 immunoreactivity and monoamine depletions in the striatum”. Journal of Pharmacology and Experimental Therapeutics 312 (1): 160–9. doi:10.1124/jpet.104.072264. PMID 15331654.
^ Polston, J. E.; Cunningham, C. S.; Rodvelt, K. R.; Miller, D. K. (2006). “Lobeline augments and inhibits cocaine-induced hyperactivity in rats”. Life Sciences 79 (10): 981–90. doi:10.1016/j.lfs.2006.05.006. PMID 16765386.
^ Farook, J. M.; Lewis, B; Gaddis, J. G.; Littleton, J. M.; Barron, S (2009). “Lobeline, a nicotinic partial agonist attenuates alcohol consumption and preference in male C57BL/6J mice”. Physiology & Behavior 97 (3–4): 503–6. doi:10.1016/j.physbeh.2009.02.031. PMID 19268674.
^ Zheng, G; Dwoskin, L. P.; Crooks, P. A. (2006). “Vesicular monoamine transporter 2: Role as a novel target for drug development”. The AAPS Journal 8 (4): E682–92. doi:10.1208/aapsj080478. PMC 2751365. PMID 17233532.
^ Zheng, F; Zheng, G; Deaciuc, A. G.; Zhan, C. G.; Dwoskin, L. P.; Crooks, P. A. (2007). “Computational neural network analysis of the affinity of lobeline and tetrabenazine analogs for the vesicular monoamine transporter-2”. Bioorganic & Medicinal Chemistry 15 (8): 2975–92. doi:10.1016/j.bmc.2007.02.013. PMC 2001191. PMID 17331733.
^ Zheng, G; Dwoskin, L. P.; Deaciuc, A. G.; Norrholm, S. D.; Crooks, P. A. (2005). “Defunctionalized lobeline analogues: Structure-activity of novel ligands for the vesicular monoamine transporter”. Journal of Medicinal Chemistry 48 (17): 5551–60. doi:10.1021/jm0501228. PMC 3617589. PMID 16107155.
^ Wilhelm, C. J.; Johnson, R. A.; Eshleman, A. J.; Janowsky, A (2008). “Lobeline effects on tonic and methamphetamine-induced dopamine release”. Biochemical Pharmacology 75 (6): 1411–5. doi:10.1016/j.bcp.2007.11.019. PMC 2435375. PMID 18191815.
^ Wilhelm, C. J.; Johnson, R. A.; Lysko, P. G.; Eshleman, A. J.; Janowsky, A (2004). “Effects of methamphetamine and lobeline on vesicular monoamine and dopamine transporter-mediated dopamine release in a cotransfected model system”. Journal of Pharmacology and Experimental Therapeutics 310 (3): 1142–51. doi:10.1124/jpet.104.067314. PMID 15102929.
^ Zheng, G; Horton, D. B.; Deaciuc, A. G.; Dwoskin, L. P.; Crooks, P. A. (2006). “Des-keto lobeline analogs with increased potency and selectivity at dopamine and serotonin transporters”. Bioorganic & Medicinal Chemistry Letters 16 (19): 5018–21. doi:10.1016/j.bmcl.2006.07.070. PMC 3934794. PMID 16905316.
^ PDB entry en:Template:PDBe. Hansen, S. B.; Sulzenbacher, G; Huxford, T; Marchot, P; Taylor, P; Bourne, Y (2005). “Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations”. The EMBO Journal 24 (20): 3635–46. doi:10.1038/sj.emboj.7600828. PMC 1276711. PMID 16193063.
^ Damaj, M. I.; Patrick, G. S.; Creasy, K. R.; Martin, B. R. (1997). “Pharmacology of lobeline, a nicotinic receptor ligand”. The Journal of Pharmacology and Experimental Therapeutics 282 (1): 410–9. PMID 9223582.
^ Miller, D. K.; Harrod, S. B.; Green, T. A.; Wong, M. Y.; Bardo, M. T.; Dwoskin, L. P. (2003). “Lobeline attenuates locomotor stimulation induced by repeated nicotine administration in rats”. Pharmacology, Biochemistry, and Behavior 74 (2): 279–86. doi:10.1016/s0091-3057(02)00996-6. PMID 12479946.
^ Miller, D. K.; Lever, J. R.; Rodvelt, K. R.; Baskett, J. A.; Will, M. J.; Kracke, G. R. (2007). “Lobeline, a potential pharmacotherapy for drug addiction, binds to mu opioid receptors and diminishes the effects of opioid receptor agonists”. Drug and Alcohol Dependence 89 (2–3): 282–91. doi:10.1016/j.drugalcdep.2007.02.003. PMID 17368966.

この項目は、薬学に関連した書きかけの項目です。この項目を加筆・訂正などしてくださる協力者を求めています（プロジェクト:薬学／Portal:医学と医療/Portal:化学）。

[1] Stead LF, Hughes JR; Hughes (2012). “Lobeline for smoking cessation”. Cochrane Database Syst Rev 2: CD000124. doi:10.1002/14651858.CD000124.pub2. PMID 22336780.

[2] Marlow, S. P.; Stoller, J. K. (2003). “Smoking cessation”. Respiratory care 48 (12): 1238–54; discussion 1254–6. PMID 14651764.

[3] Buchhalter, A. R.; Fant, R. V.; Henningfield, J. E. (2008). “Novel pharmacological approaches for treating tobacco dependence and withdrawal: Current status”. Drugs 68 (8): 1067–88. doi:10.2165/00003495-200868080-00005. PMID 18484799.

[4] Neugebauer, N. M.; Harrod, S. B.; Stairs, D. J.; Crooks, P. A.; Dwoskin, L. P.; Bardo, M. T. (2007). “Lobelane decreases methamphetamine self-administration in rats”. European Journal of Pharmacology 571 (1): 33–8. doi:10.1016/j.ejphar.2007.06.003. PMC 2104779. PMID 17612524.

[5] Eyerman, D. J.; Yamamoto, B. K. (2005). “Lobeline attenuates methamphetamine-induced changes in vesicular monoamine transporter 2 immunoreactivity and monoamine depletions in the striatum”. Journal of Pharmacology and Experimental Therapeutics 312 (1): 160–9. doi:10.1124/jpet.104.072264. PMID 15331654.

[6] Polston, J. E.; Cunningham, C. S.; Rodvelt, K. R.; Miller, D. K. (2006). “Lobeline augments and inhibits cocaine-induced hyperactivity in rats”. Life Sciences 79 (10): 981–90. doi:10.1016/j.lfs.2006.05.006. PMID 16765386.

[7] Farook, J. M.; Lewis, B; Gaddis, J. G.; Littleton, J. M.; Barron, S (2009). “Lobeline, a nicotinic partial agonist attenuates alcohol consumption and preference in male C57BL/6J mice”. Physiology & Behavior 97 (3–4): 503–6. doi:10.1016/j.physbeh.2009.02.031. PMID 19268674.

[8] Zheng, G; Dwoskin, L. P.; Crooks, P. A. (2006). “Vesicular monoamine transporter 2: Role as a novel target for drug development”. The AAPS Journal 8 (4): E682–92. doi:10.1208/aapsj080478. PMC 2751365. PMID 17233532.

[9] Zheng, F; Zheng, G; Deaciuc, A. G.; Zhan, C. G.; Dwoskin, L. P.; Crooks, P. A. (2007). “Computational neural network analysis of the affinity of lobeline and tetrabenazine analogs for the vesicular monoamine transporter-2”. Bioorganic & Medicinal Chemistry 15 (8): 2975–92. doi:10.1016/j.bmc.2007.02.013. PMC 2001191. PMID 17331733.

[10] Zheng, G; Dwoskin, L. P.; Deaciuc, A. G.; Norrholm, S. D.; Crooks, P. A. (2005). “Defunctionalized lobeline analogues: Structure-activity of novel ligands for the vesicular monoamine transporter”. Journal of Medicinal Chemistry 48 (17): 5551–60. doi:10.1021/jm0501228. PMC 3617589. PMID 16107155.

[11] Wilhelm, C. J.; Johnson, R. A.; Eshleman, A. J.; Janowsky, A (2008). “Lobeline effects on tonic and methamphetamine-induced dopamine release”. Biochemical Pharmacology 75 (6): 1411–5. doi:10.1016/j.bcp.2007.11.019. PMC 2435375. PMID 18191815.

[12] Wilhelm, C. J.; Johnson, R. A.; Lysko, P. G.; Eshleman, A. J.; Janowsky, A (2004). “Effects of methamphetamine and lobeline on vesicular monoamine and dopamine transporter-mediated dopamine release in a cotransfected model system”. Journal of Pharmacology and Experimental Therapeutics 310 (3): 1142–51. doi:10.1124/jpet.104.067314. PMID 15102929.

[13] Zheng, G; Horton, D. B.; Deaciuc, A. G.; Dwoskin, L. P.; Crooks, P. A. (2006). “Des-keto lobeline analogs with increased potency and selectivity at dopamine and serotonin transporters”. Bioorganic & Medicinal Chemistry Letters 16 (19): 5018–21. doi:10.1016/j.bmcl.2006.07.070. PMC 3934794. PMID 16905316.

[14] PDB entry en:Template:PDBe. Hansen, S. B.; Sulzenbacher, G; Huxford, T; Marchot, P; Taylor, P; Bourne, Y (2005). “Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations”. The EMBO Journal 24 (20): 3635–46. doi:10.1038/sj.emboj.7600828. PMC 1276711. PMID 16193063.

[15] Damaj, M. I.; Patrick, G. S.; Creasy, K. R.; Martin, B. R. (1997). “Pharmacology of lobeline, a nicotinic receptor ligand”. The Journal of Pharmacology and Experimental Therapeutics 282 (1): 410–9. PMID 9223582.

[16] Miller, D. K.; Harrod, S. B.; Green, T. A.; Wong, M. Y.; Bardo, M. T.; Dwoskin, L. P. (2003). “Lobeline attenuates locomotor stimulation induced by repeated nicotine administration in rats”. Pharmacology, Biochemistry, and Behavior 74 (2): 279–86. doi:10.1016/s0091-3057(02)00996-6. PMID 12479946.

[17] Miller, D. K.; Lever, J. R.; Rodvelt, K. R.; Baskett, J. A.; Will, M. J.; Kracke, G. R. (2007). “Lobeline, a potential pharmacotherapy for drug addiction, binds to mu opioid receptors and diminishes the effects of opioid receptor agonists”. Drug and Alcohol Dependence 89 (2–3): 282–91. doi:10.1016/j.drugalcdep.2007.02.003. PMID 17368966.

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依存症治療

作用機序

関連項目

出典