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分子の立体構造と生命講義　 2 回目 3-Dimensional Molecular Structure for the Life Science

分子の立体構造と生命講義　 2 回目 3-Dimensional Molecular Structure for the Life Science. 北里大学薬学部 3 年前期選択　 2008 年 4 月 -7 月　 12 回 担当者　梅山秀明、竹田 - 志鷹真由子、寺師玄記、加納和彦 毎週月曜日 4 時限　 2 ： 30-3 ： 45 　港区白金キャンパス 1501 教室 Hideaki Umeyama, Ph.D., Professor School of Pharmacy, Kitasato University

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分子の立体構造と生命講義　 2 回目 3-Dimensional Molecular Structure for the Life Science

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  1. 分子の立体構造と生命講義　2回目3-Dimensional Molecular Structure for the Life Science • 北里大学薬学部3年前期選択　2008年4月-7月　12回 • 担当者　梅山秀明、竹田-志鷹真由子、寺師玄記、加納和彦 • 毎週月曜日4時限　2：30-3：45　港区白金キャンパス1501教室 • Hideaki Umeyama, Ph.D., Professor • School of Pharmacy, Kitasato University • 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan • phone : +81-3-5791-6330 fax : +81-3-3446-9553 • e-mail:umeyamah@pharm.kitasato-u.ac.jp • 港区白金５－９－１ • 北里大学薬学部教授 • （理化学研究所客員主管研究員、東北大学未来研客員教授） • 梅山秀明 • http://famshelp.gsc.riken.jp/famsbase/index.html • http://www.pd-fams.com/index_ja.html • http://www.pharm.kitasato-u.ac.jp/bmd/files/achievement.html • http://www.pharm.kitasato-u.ac.jp/bmd/ • http://h20pharm.kitasato-u.websyllabus.jp/content/versionview/235/29

  2. メラトニン受容体作動薬ramelteon(Rozerem)睡眠障害治療薬メラトニン受容体作動薬ramelteon(Rozerem)睡眠障害治療薬 • 2005年7月22日 • アメリカ食品医薬品局（FDA)は不眠症の治療薬としてramelteonを承認。 • メラトニン受容体作動薬は従来のGABA-BZ系の薬剤とは違う

  3. 睡眠障害治療薬 • 武田薬品工業は原発性不眠症、概日リズム睡眠障害薬として、 • メラトニン受容体作動薬ramelteon(Rozerem)を、メラトニン構造を基に、 • メラトニン受容体（Melatonin receptors）の中でも、ML3に結合せず、 ML1 とML2に結合する化合物を創製した。 • 日本では、2005年に29万人が睡眠障害を抱えている（米国は2004年に4200万人が不眠症）。

  4. メラトニン受容体作動薬ramelteon(Rozerem)武田薬品工業　原発性不眠症、概日リズム睡眠障害メラトニン受容体作動薬ramelteon(Rozerem)武田薬品工業　原発性不眠症、概日リズム睡眠障害

  5. Ramelteon :melatonin receptor agonist • Ramelteon is a melatonin receptor agonist with both high affinity for • melatonin MT1 and • MT2 receptors and • selectivity over the MT3 receptor. • Ramelteon demonstrates full agonist activity in vitro in cells expressing human MT1 or MT2 receptors, • and high selectivity for human MT 1 and MT2 receptors compared to the MT3 receptor.

  6. Ramelteon • IUPAC Name: N-[2-[(8S)-2,6,7,8-tetrahydro-1H-cyclopenta[e][1]benzoxol-8-yl]ethyl]propanamideCanonical SMILES: CCC(=O)NCCC1CCC2=C1C3=C(C=C2)OCC3Isomeric SMILES: CCC(=O)NCC[C@@H]1CCC2=C1C3=C(C=C2)OCC3InChI: InChI=1/C16H21NO2/c1-2-15(18)17-9-7-12-4-3-11-5-6-14-13(16(11)12)8-10-19-14/h5-6,12H,2-4,7-10H2,1H3,(H,17,18)/t12-/m0/s1/f/h17H

  7. メラトニンとその受容体 • メラトニン受容体ML1 とML2受容体は視交叉上核と網膜だけに発現して、 • メラトニン受容体作動薬は、 • GABA-BZ系に比べて狭い範囲にある標的に結合。 • GABA-BZ系の薬剤でよく起こる薬物依存性の副作用が軽くなることが期待される。

  8. Melatonin • Melatonin, 5-methoxy-N-acetyltryptamine, is a naturally occurring hormone found in most animals and some of other living organisms, including 藻類(algae) and humans, at levels that vary in a daily cycle. • It plays a role in the regulation of the概日リズム（Circadian rhythm）of several biological functions.[2] • Many biological effects of melatonin are produced through activation of melatonin receptors.

  9. メラトニン • メラトニン快眠に, 松果体で作られ血液中に放出されたメラトニンは、視交叉上核（しこうさじょうかく）にあるメラトニン受容体に結合すると、 • 体温を下げ、眠気を起こすことが確認されている。 • ところが、夜中に仕事をしたりすると、夜になっても光が目に入り、メラトニンが放出されない 。 • メラトニンは体内時計の調節を担う物質として知られ、夜間に多く分泌され、睡眠を促し体を休ませる。

  10. Melatonin • IUPAC Name: N-[2-(5-methoxy-1H-indol-3-yl)ethyl]acetamideCanonical SMILES: CC(=O)NCCC1=CNC2=C1C=C(C=C2)OCInChI: InChI=1/C13H16N2O2/c1-9(16)14-6-5-10-8-15-13-4-3-11(17-2)7-12(10)13/h3-4,7-8,15H,5-6H2,1-2H3,(H,14,16)/f/h14H

  11. Melatonin receptor type 1A (Mel-1A-R) (Mel1a melatonin receptor) • [FUNCTION] High affinity receptor for melatonin. Likely to mediates the reproductive and circadian actions of melatonin. The activity of this receptor is mediated by 百日咳毒素(pertussis toxin ) • sensitive G proteins that inhibit adenylate cyclase activity. • Circadian rhythm　外界と完全に無関係に自分の体内リズム • Reproductive Science　（復元的）生殖科学研究 • 睡眠サイクルの正常化 • 眠りと覚醒の周期を調整することで、睡眠に直接作用します。 • メラトニン（Melatonin）は昼と夜の周期に反応して脳の松果体から分泌され、体の日内リズムを調整しているホルモン • [SUBCELLULAR LOCATION] Cell membrane; Multi-pass membrane protein. • [TISSUE SPECIFICITY] Hippocampus. 「海馬（hippocampus）」 • [SIMILARITY] Belongs to the G-protein coupled receptor 1 family. • [WEB RESOURCE] Name=Wikipedia; Note=Melatonin receptor entry; URL='http://en.wikipedia.org/wiki/Melatonin_receptor'.

  12. P48039 MTR1A_HUMANP49286 MTR1B_HUMANQ13585 MTR1L_HUMAN

  13. Melatonin receptor type 1A (Mel-1A-R) (Mel1a melatonin receptor) • [FUNCTION] High affinity receptor for melatonin. Likely to mediates the reproductive and circadian actions of melatonin. The activity of this receptor is mediated by 百日咳毒素(pertussis toxin ) • sensitive G proteins that inhibit adenylate cyclase activity. • [SUBCELLULAR LOCATION] Cell membrane; Multi-pass membrane protein. • [TISSUE SPECIFICITY] Hippocampus. 「海馬（hippocampus）」 • [SIMILARITY] Belongs to the G-protein coupled receptor 1 family. • [WEB RESOURCE] Name=Wikipedia; Note=Melatonin receptor entry; URL='http://en.wikipedia.org/wiki/Melatonin_receptor'.

  14. P48039MTR1A_HUMAN • >gi|1346544|sp|P48039.1|MTR1A_HUMAN Melatonin receptor type 1A (Mel-1A-R) (Mel1a melatonin receptor)MQGNGSALPNASQPVLRGDGARPSWLASALACVLIFTIVVDILGNLLVILSVYRNKKLRNAGNIFVVSLAVADLVVAIYPYPLVLMSIFNNGWNLGYLHCQVSGFLMGLSVIGSIFNITGIAINRYCYICHSLKYDKLYSSKNSLCYVLLIWLLTLAAVLPNLRAGTLQYDPRIYSCTFAQSVSSAYTIAVVVFHFLVPMIIVIFCYLRIWILVLQVRQRVKPDRKPKLKPQDFRNFVTMFVVFVLFAICWAPLNFIGLAVASDPASMVPRIPEWLFVASYYMAYFNSCLNAIIYGLLNQNFRKEYRRIIVSLCTARVFFVDSSNDVADRVKWKPSPLMTNNNVVKVDSV

  15. Sequence identities of melatonin receptors • 1e-100(350,1-350)100% • ref|NP_005949.1| melatonin receptor 1A [Homo sapiens] gb|AAH74947.1| Melatonin receptor 1A [Homo sapiens] gb|AAH74946.1| Melatonin receptor 1A [Homo sapiens] dbj|BAA85303.1| melatonin 1a receptor [Homo sapiens] sp|P48039 spncbi|MTR1A_HUMAN Melatonin receptor type 1A (Mel-1A-R) (Mel1a melatonin receptor) gb|AAB17720.1| Mel-1a melatonin receptor; Length=350 • 7e-83(319,23-341)62% • ref|NP_005950.1| melatonin receptor 1B [Homo sapiens] gb|AAH69163.1| Melatonin receptor 1B [Homo sapiens] gb|AAS00461.1| melatonin receptor 1B [Homo sapiens] dbj|BAA92315.1| melatonin 1b receptor [Homo sapiens] sp|P49286 spncbi|MTR1B_HUMAN Melatonin receptor type 1B (Mel-1B-R) (Mel1b melatonin receptor) gb|AAC50612.1| Mel1b-melatonin receptor; Length=362 • 1e-86(296,24-319)52% • ref|NP_004215.1| G protein-coupled receptor 50 [Homo sapiens] sp|Q13585 spncbi|MTR1L_HUMAN Melatonin-related receptor (G protein-coupled receptor 50) (H9) gb|AAC50614.1| melatonin-related receptor; Length=613 • 5e-47(300,7-306)25% • gb|AAH13780.1| Adenosine A2a receptor [Homo sapiens] ref|NP_000666.2| adenosine A2a receptor [Homo sapiens] gb|AAN01273.1| adenosine receptor A2a [Homo sapiens] gb|AAP35645.1| adenosine A2a receptor [Homo sapiens] gb|AAA83270.1| A2a adenosine receptor subtype [Homo sapiens] emb|CAA48504.1| A2a adenosine receptor [Homo sapiens] gb|AAX41777.1| adenosine A2a receptor [synthetic construct] emb|CAG30253.1| ADORA2A [Homo sapiens] sp|P29274 spncbi|AA2AR_HUMAN Adenosine A2a receptor; Length=412

  16. Ramelteon; Rozerem • Ramelteon; Rozerem; Rozerem (TN) ... • MW: 259.343440 g/mol | MF: C16H21NO2 • IUPAC Name: N-[2-[(8S)-2,6,7,8-tetrahydro-1H-cyclopenta[e][1]benzoxol-8-yl]ethyl]propanamideCanonical SMILES: CCC(=O)NCCC1CCC2=C1C3=C(C=C2)OCC3Isomeric SMILES: CCC(=O)NCC[C@@H]1CCC2=C1C3=C(C=C2)OCC3

  17. Melatonin; Melatonine • CID: 896 • IUPAC: N-[2-(5-methoxy-1H-indol-3-yl)ethyl]acetamide • MW: 232.278340 g/mol | MF: C13H16N2O2 • IUPAC Name: N-[2-(5-methoxy-1H-indol-3-yl)ethyl]acetamideCanonical SMILES: CC(=O)NCCC1=CNC2=C1C=C(C=C2)OC • Molecular Weight: 232.27834 g/molMolecular Formula: C13H16N2O2XLogP: 1.6Hydrogen Bond Donor Count: 2Hydrogen Bond Acceptor Count: 3Rotatable Bond Count: 4Tautomer Count: 2

  18. Melatonin receptor type 1B (Mel-1B-R) • >gi|1346548|sp|P49286.1|MTR1B_HUMAN Melatonin receptor type 1B (Mel-1B-R) (Mel1b melatonin receptor) • MSENGSFANCCEAGGWAVRPGWSGAGSARPSRTPRPPWVAPALSAVLIVTTAVDVVGNLLVILSVLRNRKLRNAGNLFLVSLALADLVVAFYPYPLILVAIFYDGWALGEEHCKASAFVMGLSVIGSVFNITAIAINRYCYICHSMAYHRIYRRWHTPLHICLIWLLTVVALLPNFFVGSLEYDPRIYSCTFIQTASTQYTAAVVVIHFLLPIAVVSFCYLRIWVLVLQARRKAKPESRLCLKPSDLRSFLTMFVVFVIFAICWAPLNCIGLAVAINPQEMAPQIPEGLFVTSYLLAYFNSCLNAIVYGLLNQNFRREYKRILLALWNPRHCIQDASKGSHAEGLQSPAPPIIGVQHQADAL

  19. Sequence identities of Melatonin receptors • 5e-94(362,1-362)100% • ref|NP_005950.1| melatonin receptor 1B [Homo sapiens] gb|AAH69163.1| Melatonin receptor 1B [Homo sapiens] gb|AAS00461.1| melatonin receptor 1B [Homo sapiens] dbj|BAA92315.1| melatonin 1b receptor [Homo sapiens] sp|P49286 spncbi|MTR1B_HUMAN Melatonin receptor type 1B (Mel-1B-R) (Mel1b melatonin receptor) gb|AAC50612.1| Mel1b-melatonin receptor; Length=362 • 3e-86(337,9-345)59% • ref|NP_005949.1| melatonin receptor 1A [Homo sapiens] gb|AAH74947.1| Melatonin receptor 1A [Homo sapiens] gb|AAH74946.1| Melatonin receptor 1A [Homo sapiens] dbj|BAA85303.1| melatonin 1a receptor [Homo sapiens] sp|P48039 spncbi|MTR1A_HUMAN Melatonin receptor type 1A (Mel-1A-R) (Mel1a melatonin receptor) gb|AAB17720.1| Mel-1a melatonin receptor; Length=350 • 4e-85(315,1-315)47% • ref|NP_004215.1| G protein-coupled receptor 50 [Homo sapiens] sp|Q13585 spncbi|MTR1L_HUMAN Melatonin-related receptor (G protein-coupled receptor 50) (H9) gb|AAC50614.1| melatonin-related receptor; Length=613

  20. Melatonin-related receptor (G protein-coupled receptor 50) • >gi|2494977|sp|Q13585.1|MTR1L_HUMAN Melatonin-related receptor (G protein-coupled receptor 50) (H9)MGPTLAVPTPYGCIGCKLPQPEYPPALIIFMFCAMVITIVVDLIGNSMVILAVTKNKKLRNSGNIFVVSLSVADMLVAIYPYPLMLHAMSIGGWDLSQLQCQMVGFITGLSVVGSIFNIVAIAINRYCYICHSLQYERIFSVRNTCIYLVITWIMTVLAVLPNMYIGTIEYDPRTYTCIFNYLNNPVFTVTIVCIHFVLPLLIVGFCYVRIWTKVLAARDPAGQNPDNQLAEVRNFLTMFVIFLLFAVCWCPINVLTVLVAVSPKEMAGKIPNWLYLAAYFIAYFNSCLNAVIYGLLNENFRREYWTIFHAMRHPIIFFPGLISDIREMQEARTLARARAHARDQAREQDRAHACPAVEETPMNVRNVPLPGDAAAGHPDRASGHPKPHSRSSSAYRKSASTHHKSVFSHSKAASGHLKPVSGHSKPASGHPKSATVYPKPASVHFKGDSVHFKGDSVHFKPDSVHFKPASSNPKPITGHHVSAGSHSKSAFSAATSHPKPIKPATSHAEPTTADYPKPATTSHPKPAAADNPELSASHCPEIPAIAHPVSDDSDLPESASSPAAGPTKPAASQLESDTIADLPDPTVVTTSTNDYHDVVVVDVEDDPDEMAV

  21. Sequence Identities of MTR1L Melatonin-related receptor • 0.0(613,1-613)100% • ref|NP_004215.1| G protein-coupled receptor 50 [Homo sapiens] sp|Q13585 spncbi|MTR1L_HUMAN Melatonin-related receptor (G protein-coupled receptor 50) (H9) gb|AAC50614.1| melatonin-related receptor; Length=613FAMD • 1e-101(328,22-349)47% • ref|NP_005949.1| melatonin receptor 1A [Homo sapiens] gb|AAH74947.1| Melatonin receptor 1A [Homo sapiens] gb|AAH74946.1| Melatonin receptor 1A [Homo sapiens] dbj|BAA85303.1| melatonin 1a receptor [Homo sapiens] sp|P48039 spncbi|MTR1A_HUMAN Melatonin receptor type 1A (Mel-1A-R) (Mel1a melatonin receptor) gb|AAB17720.1| Mel-1a melatonin receptor; Length=350FAMD • 1e-92(332,20-351)44% • ref|NP_005950.1| melatonin receptor 1B [Homo sapiens] gb|AAH69163.1| Melatonin receptor 1B [Homo sapiens] gb|AAS00461.1| melatonin receptor 1B [Homo sapiens] dbj|BAA92315.1| melatonin 1b receptor [Homo sapiens] sp|P49286 spncbi|MTR1B_HUMAN Melatonin receptor type 1B (Mel-1B-R) (Mel1b melatonin receptor) gb|AAC50612.1| Mel1b-melatonin receptor; Length=362FAMD

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