モノアミン受容体阻害による膵β細胞からのインスリン分泌抑制機序に関する研究

概要







༤ ኈ ㄽ ᩥ





ࣔࣀ࢔࣑ࣥཷᐜయ㜼ᐖ࡟ࡼࡿ⮅ β ⣽⬊࠿ࡽࡢ
࢖ࣥࢫࣜࣥศἪᢚไᶵᗎ࡟㛵ࡍࡿ◊✲




























ᗈᓥ኱Ꮫ኱Ꮫ㝔་ṑ⸆ಖ೺Ꮫ◊✲⛉ ་ṑ⸆Ꮫᑓᨷ


⑓㝔⸆๣Ꮫ◊✲ᐊ       


ᖹᡂ  ᖺᗘධᏛ  㛗⏣ 㯞ኸ


୺ᣦᑟᩍဨ     ᯇᑿ ⿱ᙲ

┠ḟ
1

ᗎㄽ

ᮏㄽ
1. ࣁ࣒ࢫࢱ࣮⏤᮶⮅ β ⣽⬊ᰴ (HIT-T15) ⣽⬊࡟࠾ࡅࡿྛࣔࣀ࢔࣑ࣥཷᐜయ
ࡢⓎ⌧ゎᯒ

7

2. HIT-T15 ⣽⬊ࢆ⏝࠸ࡓ࢖ࣥࢫࣜࣥศἪኚືࡢホ౯

10

3. HIT-T15 ⣽⬊࠿ࡽࡢ࢖ࣥࢫࣜࣥศἪ࡟࠾ࡼࡰࡍ࢜ࣛࣥࢨࣆࣥࡢᙳ㡪

11

4. HIT-T15 ⣽⬊࠿ࡽࡢ࢖ࣥࢫࣜࣥศἪ࡟࠾ࡼࡰࡍ࢜ࣛࣥࢨࣆࣥ 30 ᪥㛫᭚㟢
ࡢᙳ㡪

13

5. HIT-T15 ⣽⬊࡟࠾ࡅࡿ࢜ࣛࣥࢨࣆࣥ࡟ࡼࡿ⣽⬊ẘᛶࡢ☜ㄆ

15

6. HIT-T15 ⣽⬊࠿ࡽࡢ࢖ࣥࢫࣜࣥศἪ࡟࠾ࡅࡿࢻࣃ࣑ࣥཷᐜయࡢ㛵୚

16

7. HIT-T15 ⣽⬊࠿ࡽࡢ࢖ࣥࢫࣜࣥศἪ࡟࠾ࡅࡿࢭࣟࢺࢽࣥཷᐜయࡢ㛵୚

22

8. HIT-T15 ⣽⬊࠿ࡽࡢ࢖ࣥࢫࣜࣥศἪ࡟࠾ࡅࡿࣄࢫࢱ࣑ࣥཷᐜయࡢ㛵୚

27

9. HIT-T15 ⣽⬊࡟࠾ࡅࡿྛࣔࣀ࢔࣑ࣥཷᐜయ㛵㐃⸆࡟ࡼࡿ⣽⬊ẘᛶࡢ☜ㄆ

31

⤖ㄽ

33

ㅰ㎡

34

ᐇ㦂᪉ἲ

35

ㄽᩥ┠㘓

42

ཧ⪃ᩥ⊩

43

␎ྕ୍ぴ
AC
ADP
ANOVA
ATP
cAMP
cDNA
BSA
DAG
DNA
DMSO
DPA
DTP
EC50
EDTA
ELISA
Epac2
ER
FBS
GDP
GIP
GLP-1
GLU
GLUT
G6P
Ham’s F12K
HBSS
HRP
IP3
Kir
LMW
MARTA
mRNA
NMDA
PBS
PC
PCR
2-PEA
PIP2
PKA
PKC
PLC
PMS
PNGase
PVDF
SD
SDA

: adenylate cyclase
: adenosine diphosphate
: analysis of variance
: adenosine triphosphate
: cyclic adenosine monophosphate
: complementary deoxyribonucleic acid
: bovine serum albumin
: diacylglycerol
: deoxyribonucleic acid
: dimethyl sulfoxide
: dopamine partial agonist
: guanosine triphosphate
: half maximal effective concentration
: ethylenediaminetetraacetic acid
: enzyme-linked immuno sorbent assay
: exchange protein directly activated by cAMP 2
: endoplasmic reticulum
: fetal bovine serum
: guanosine diphosphate
: gastric inhibitory polypeptide
: glucagon-like peptide-1
: glucose
: glucose transporter
: glucose-6-phosphate
: Nutrient Mixture F-12 Ham Kaighn’s modification
: Hank’s balanced salts
: horseradish peroxidase
: inositol trisphosphate
: inward-rectifier potassium channel
: low molecular weight
: multi-acting receptor targeted antipsychotics
: messenger ribonucleic acid
: N-methyl-D-aspartate
: Dulbecco’s phosphate buffered saline
: prohormone convertase
: polymerase chain reaction
: 2-pyridylethylamine
: phosphatidylinositol bisphosphate
: protein kinase A
: protein kinase C
: phospholipase C
: N-methyl dibenzopyrazine methylsulfate
: peptide-N-glycosidase
: polyvinylidene difluoride
: standard deviation
: serotonin-dopamine antagonist

SDS-PAGE
SERCA
SNAP25
SUR
TAE
TBS
UV
VDCC
XTT

: polyacrylamide gel electrophoresis
: sarco/endoplasmic reticulum Ca2+-ATPase
: synaptosomal nerve-associated protein 25
: sulfonylurea receptor
: Tris-acetate-EDTA
: Tris buffered saline
: ultraviolet
: voltage-dependent Ca2+ channel
: sodium 3’-[1(-phenylaminocarbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro) benzene
sulfonic acid hydrate

ᗎㄽ
⤫ྜኻㄪ⑕ࡣ 10㹼30 ௦ࡢ㟷ᖺᮇ࡟ዲⓎࡍࡿෆᅉᛶ⢭⚄⑌ᝈࡢ୍✀࡛࠶ࡿࠋMcGrath ࡽࡢㄪᰝ
࡟ࡼࡿ࡜ࠊ⤫ྜኻㄪ⑕ࡢ⏕ᾭ⨯ᝈ⋡ࡣ 0.7%࡜ሗ࿌ࡉࢀ࡚࠸ࡿ (1)ࠋࡲࡓࠊཌ⏕ປാ┬࡟ࡼࡿ 2017
ᖺࡢᝈ⪅ㄪᰝ࡛ࡣࠊ⤫ྜኻㄪ⑕࡟ࡼࡾ་⒪ᶵ㛵ࢆཷデࡋ࡚࠸ࡿᝈ⪅ࡢᩘࡣ 79.2 ୓ே࡟┦ᙜࡍࡿ࡜
᥎ ࡉࢀ࡚࠸ࡿ (2)ࠋ⤫ྜኻㄪ⑕ࡢ⑓ែࡣ᫂ࡽ࠿࡟ࡉࢀ࡚࠸࡞࠸࡜ࡇࢁࡶከ࠸ࡀࠊࡇࢀࡲ࡛࡟ࠊ⤫
ྜኻㄪ⑕ࡢ἞⒪࡟⏝࠸ࡽࢀࡿᢠ⢭⚄⑓⸆ࡢ⮫ᗋ⏝㔞࡜ࢻࣃ࣑ࣥ D2 ཷᐜయࡢ㐽᩿స⏝࡟ᑐࡍࡿຊ౯
ࡢ┦㛵ᛶࡀ㧗࠸ࡇ࡜ࡸ (3)ࠊࢻࣃ࣑ࣥཷᐜయ่⃭⸆࡛࠶ࡿ࢔ࣥࣇ࢙ࢱ࣑ࣥࡸ࣓ࢱࣥࣇ࢙ࢱ࣑ࣥࡢ୰
ẘ⪅ࡀ⤫ྜኻㄪ⑕ᵝࡢ⑕≧ࢆ࿊ࡋࠊࡑࡢ⑕≧ࡣᢠ⢭⚄⑓⸆ࡢᢞ୚࡟ࡼࡗ࡚ᢚไࡉࢀࡿࡇ࡜࡞࡝ࡀ
ሗ࿌ࡉࢀ࡚࠸ࡿ (4, 5)ࠋࡲࡓࠊLaruelle ࡽࡣࠊ⤫ྜኻㄪ⑕ᝈ⪅ࡣ೺ᖖ⪅࡜ẚ㍑ࡋ࡚ࢻࣃ࣑ࣥࡢᨺฟ
㔞ࡀ⣙ 2 ಸ࡟ቑຍࡋ࡚࠸ࡿࡇ࡜ࢆᐇドࡋ࡚࠸ࡿ (6)ࠋࡇࢀࡽࡢሗ࿌࠿ࡽࠊ⌧ᅾ࡛ࡣࠕࢻࣃ࣑ࣥ௬
ㄝࠖࡀ⤫ྜኻㄪ⑕ࡢ⑓ែࢆㄝ᫂ࡍࡿ᭱ࡶ᭷ຊ࡞ㄝ࡜⪃࠼ࡽࢀ࡚࠸ࡿࠋࠕࢻࣃ࣑ࣥ௬ㄝࠖࡣࠊ⬻ᖿ
㒊࡟Ꮡᅾࡍࡿࢻࣃ࣑ࣥ⣔⚄⤒ࡢ⚄⤒᰾࠿ࡽ⬻ࡢྛ㒊఩࡟ᢞᑕࡍࡿࢻࣃ࣑ࣥ⤒㊰࡟࠾ࡅࡿఏ㐩㞀ᐖ
ࡀ⤫ྜኻㄪ⑕ࡢ⑕≧ࢆច㉳ࡍࡿࡇ࡜ࢆᥦၐࡋࡓㄝ࡛࠶ࡿࠋ౛࠼ࡤࠊ୰⬻⭡ഃ⿕⵹㔝࠿ࡽ㎶⦕⣔ࡢ
ഃᆘ᰾࡟⮳ࡿࢻࣃ࣑ࣥ⤒㊰ (୰⬻㎶⦕⣔) ࡟࠾ࡅࡿ D2 ཷᐜయࡢ㐣๫࡞่⃭ஹ㐍ࡣࠊዶ᝿ࡸᗁぬ࡞࡝
ࡢ㝧ᛶ⑕≧ࢆច㉳ࡍࡿࡢ࡟ᑐࡋࠊ୰⬻⭡ഃ⿕⵹㔝࠿ࡽ๓㢌ⴥ⓶㉁࡟⮳ࡿࢻࣃ࣑ࣥ⤒㊰ (୰⬻⓶㉁
⣔) ࡟࠾ࡅࡿ D1 ཷᐜయࡢ่⃭ᢚไࡣࠊពḧࡢపୗࡸឤ᝟ࡢ㕌㯞ࠊ↓Ⅽ࡞࡝ࡢ㝜ᛶ⑕≧ࡸㄆ▱ᶵ⬟
㞀ᐖࢆច㉳ࡍࡿせᅉ࡜⪃࠼ࡽࢀ࡚࠸ࡿࠋࢻࣃ࣑ࣥ௬ㄝ࡟ຍ࠼࡚ࠊN-࣓ࢳࣝ-D-࢔ࢫࣃࣛࢠࣥ㓟
(NMDA) ཷᐜయࡢ㠀➇ྜⓗᣕᢠ⸆࡛࠶ࡿࣇ࢙ࣥࢩࢡࣜࢪࣥࡸࢣࢱ࣑ࣥࡢ୰ẘ⪅ࡀ⤫ྜኻㄪ⑕ᵝࡢ
⑕≧ࢆ࿊ࡍࡿࡇ࡜ࡸ (7)ࠊࢢࣝࢱ࣑ࣥ㓟ࡀ NMDA ཷᐜయ࡟⤖ྜࡍࡿࡇ࡜࠿ࡽࠊࢻࣃ࣑ࣥ࡟౫Ꮡࡋ
࡞࠸⚄⤒ఏ㐩ࡢㄪ⠇୙඲࡟ࡼࡗ࡚⤫ྜኻㄪ⑕ࡢ⑕≧ࡀⓎ⑕ࡍࡿࡇ࡜ࢆᥦၐࡋࡓࠕࢢࣝࢱ࣑ࣥ㓟ఏ
㐩పୗ௬ㄝࠖ(8) ࡸࠕNMDA ཷᐜయᶵ⬟పୗ௬ㄝࠖ(9) ࡶ⤫ྜኻㄪ⑕ࡢ⑓ែࢆㄝ᫂ࡍࡿㄝ࡜⪃࠼ࡽ
ࢀ࡚࠸ࡿࠋ
  ⤫ྜኻㄪ⑕ࡢ἞⒪ࡣࠊᢠ⢭⚄⑓⸆ࢆ⏝࠸ࡓ⸆≀⒪ἲࡀ୰ᚰ࡜࡞ࡿࠋ᭱ࡶྂ࠸ᢠ⢭⚄⑓⸆࡛࠶
ࡿࢡࣟࣝࣉ࣐ࣟࢪࣥࡀ 1951 ᖺ࡟ྜᡂࡉࢀࠊ⩣ 1952 ᖺ࡟ࡣ࢖ࣥࢻ⺬ᮌ (Rauwolfia serpentina) ࡼࡾࣞ
ࢭࣝࣆࣥࡀ࢔ࣝ࢝ࣟ࢖ࢻ࡜ࡋ࡚ᢳฟࡉࢀ࡚࠸ࡿ (10)ࠋࡑࡢᚋࠊࢡࣟࣝࣉ࣐ࣟࢪࣥࢆྵࡴࣇ࢙ࣀࢳ
࢔ࢪࣥㄏᑟయࡣࢻࣃ࣑ࣥ D2 ཷᐜయ࡟ᑐࡍࡿ㐽᩿స⏝ࠊࣞࢭࣝࣆࣥࡣࢻࣃ࣑ࣥࡸࣀࣝ࢔ࢻࣞࢼࣜࣥ
࡞࡝ࡢࣔࣀ࢔࣑ࣥࢆࢩࢼࣉࢫᑠ⬊ෆ࡛ᯤῬࡉࡏࡿస⏝ࢆ♧ࡍࡇ࡜ࡀ᫂ࡽ࠿࡟࡞ࡗࡓࠋࢡࣟࣝࣉࣟ
࣐ࢪࣥࡸࣞࢭࣝࣆࣥࡀ㛤Ⓨࡉࢀ࡚௨㝆ࠊࣈࢳࣟࣇ࢙ࣀࣥㄏᑟయ࡛࠶ࡿࣁࣟ࣌ࣜࢻ࣮ࣝ࡞࡝ᙉຊ࡞
D2 ཷᐜయ㐽᩿స⏝ࢆ᭷ࡍࡿᐃᆺᢠ⢭⚄⑓⸆ࡀከࡃ㛤Ⓨࡉࢀࠊ⮫ᗋ⌧ሙ࡛౑⏝ࡉࢀࡿ࡟⮳ࡗࡓ
(Table 1) (11-13)ࠋᐃᆺᢠ⢭⚄⑓⸆ࡢᙉຊ࡞ D2 ཷᐜయ㐽᩿స⏝ࡣࠊ⤫ྜኻㄪ⑕ࡢ㝧ᛶ⑕≧࡟ᑐࡋ࡚
Ⰻዲ࡞ᨵၿຠᯝࢆࡶࡓࡽࡍࡢ࡟ᑐࡋ࡚ࠊ㝜ᛶ⑕≧ࡸㄆ▱ᶵ⬟㞀ᐖ࡟ᑐࡍࡿᨵၿຠᯝࡣప࠸ࠋࡲ
ࡓࠊᐃᆺᢠ⢭⚄⑓⸆ࡣ㯮㉁⥺᮲య⣔ࡸ₃ᩯୗᆶయ⣔࡞࡝⤫ྜኻㄪ⑕ࡢ⑕≧࡜㛵㐃ࡀప࠸ࢻࣃ࣑ࣥ
⤒㊰ࡢᶵ⬟ࡶᙉࡃᢚไࡍࡿࡇ࡜࡛ࠊ㗹యእ㊰⑕≧ࡸ㧗ࣉࣟࣛࢡࢳࣥ⾑⑕࡞࡝ࡢ๪స⏝ࢆច㉳ࡍࡿ

1

ࡇ࡜࠿ࡽᚸᐜᛶࡀప࠸ࡇ࡜ࡀၥ㢟࡜ࡋ࡚ᣲࡆࡽࢀࡿࠋࡇࢀࡽࡢၥ㢟ࢆゎỴࡍࡿࡁࡗ࠿ࡅ࡜࡞ࡗࡓ
ࡢࡣࠊ1958 ᖺࡢࢡࣟࢨࣆࣥࡢྜᡂ࡛࠶ࡗࡓࠋࢡࣟࢨࣆࣥࡣᐃᆺᢠ⢭⚄⑓⸆ࡢḞⅬ࡛࠶ࡗࡓ㗹యእ
㊰⑕≧ࡢண㜵࡜㝜ᛶ⑕≧࣭ㄆ▱ᶵ⬟㞀ᐖ࡞࡝ࡢ⑕≧࡟ᑐࡍࡿᨵၿస⏝ࢆ࠶ࡿ⛬ᗘඞ᭹ࡋࡓ⸆๣࡛
࠶ࡿࠋࡑࡢᚋࡢ⸆⌮Ꮫⓗ◊✲࡟ࡼࡾࠊࢡࣟࢨࣆࣥࡣ D2 ཷᐜయࡢ㐽᩿స⏝࡟ຍ࠼࡚ࠊࢭࣟࢺࢽࣥ 5HT2A ཷᐜయ࡟ᑐࡍࡿ㐽᩿స⏝ࢆ᭷ࡋ࡚࠸ࡿࡇ࡜ࡀ᫂ࡽ࠿࡜࡞ࡗࡓࠋࡇࡢⓎぢࢆࡶ࡜࡟ࠊᐃᆺᢠ⢭
⚄⑓⸆࡜ྠ➼௨ୖࡢ㝧ᛶ⑕≧ᨵၿస⏝ࢆ⥔ᣢࡋࠊ㗹యእ㊰⑕≧ࡢண㜵࡜㝜ᛶ⑕≧࣭ㄆ▱ᶵ⬟㞀ᐖ
࡟ᑐࡍࡿᨵၿస⏝ࢆ᭷ࡍࡿ⸆๣ࡢ㛤Ⓨࡀ⾜ࢃࢀࠊ1984 ᖺ࡟ࢭࣟࢺࢽ࣭ࣥࢻࣃ࣑ࣥ㐽᩿⸆ (SDA) ࡛
࠶ࡿࣜࢫ࣌ࣜࢻࣥࡀྜᡂࡉࢀࡓࠋࡑࡢᚋࠊࢻࣃ࣑ࣥࡸࢭࣟࢺࢽࣥࡢཷᐜయ㐽᩿స⏝࡟ຍ࠼࡚ࠊࣄ
ࢫࢱ࣑ࣥࡸ࢔ࢻࣞࢼࣜࣥ࡞࡝ࡢࣔࣀ࢔࣑ࣥཷᐜయࠊ࣒ࢫ࢝ࣜࣥᛶ࢔ࢭࢳࣝࢥࣜࣥཷᐜయ࡟ᑐࡍࡿ
㐽᩿స⏝ࢆ௜୚ࡋࡓከඖཷᐜయᶆⓗᢠ⢭⚄⑓⸆ (MARTA) ࡸࢻࣃ࣑ࣥཷᐜయ㒊ศసື⸆ (DPA) ࡞
࡝ࡢ㠀ᐃᆺᢠ⢭⚄⑓⸆ࡀ㛤Ⓨࡉࢀࠊ⌧ᅾ࡛ࡣ⤫ྜኻㄪ⑕ࡢ➨୍㑅ᢥ⸆࡜ࡋ࡚౑⏝ࡉࢀ࡚࠸ࡿ
(Table 1) ࠋ

Fig. 1. Structure of olanzapine.
 ࢜ࣛࣥࢨࣆࣥ (Fig. 1) ࡣ MARTA ࡢ୍ࡘ࡛࠶ࡾࠊࣔࣀ࢔࣑ࣥཷᐜయࡸ࣒ࢫ࢝ࣜࣥᛶ࢔ࢭࢳࣝࢥ
ࣜࣥཷᐜయࢆ㐽᩿ࡍࡿࡇ࡜࡛㝧ᛶ⑕≧࡜㝜ᛶ⑕≧ࠊㄆ▱㞀ᐖࡢᨵၿຠᯝࢆ♧ࡍ (Table 2) ࠋ2013 ᖺ
࡟⾜ࢃࢀࡓฎ᪉ゎᯒㄪᰝ࡛ࠊ࢜ࣛࣥࢨࣆࣥࡣ᪥ᮏ࡜࢝ࢼࢲ࡛᭱ࡶ౑⏝ࡉࢀ࡚࠸ࡿ㠀ᐃᆺᢠ⢭⚄⑓
⸆࡛࠶ࡿ࡜ሗ࿌ࡉࢀ࡚࠸ࡿ (14-16)ࠋ୍᪉ࠊ࢜ࣛࣥࢨࣆࣥࡢᢞ୚ࡣࡋࡤࡋࡤ㧗⾑⢾࡟㉳ᅉࡍࡿ㔜⠜
࡞⢾ᒀ⑓ᛶࢣࢺ࢔ࢩࢻ࣮ࢩࢫࢆច㉳ࡍࡿࡇ࡜ࡀሗ࿌ࡉࢀ࡚࠸ࡿ (17) ࠋᮏ㑥࡛ࡣࠊ࢜ࣛࣥࢨࣆࣥࢆ
᭹⏝ࡋࡓ 3753 ౛୰ 8 ౛࡛⢾ᒀ⑓ᛶࢣࢺ࢔ࢩࢻ࣮ࢩࢫࡀច㉳ࡉࢀࠊࡑࡢ࠺ࡕ 2 ౛ࡢᝈ⪅ࡀṚஸࡋࡓ
ࡇ࡜ࡀሗ࿌ࡉࢀ࡚࠸ࡿࠋࡇࡢ஦ែࢆཷࡅ࡚ࠊཌ⏕ປാ┬ࡣ 2002 ᖺ࡟࢜ࣛࣥࢨࣆࣥࡢᢞ୚࡟ࡼࡿ㔜
⠜࡞㧗⾑⢾ࡢࣜࢫࢡ࡟㛵ࡍࡿ⥭ᛴᏳ඲ᛶ᝟ሗࢆⓎ⾲ࡋ࡚࠸ࡿ (18)ࠋᢠ⢭⚄⑓⸆ࡢ౑⏝࡟ࡼࡿ⾑⢾
್␗ᖖࡢⓎ⑕࡟ࡘ࠸࡚ࡣࠊ⢾ᒀ⑓ࡢ᪤ Ṕࢆ᭷ࡍࡿᝈ⪅ࢆ୰ᚰ࡟ᐃᆺࠊ㠀ᐃᆺ࡟㛵ಀ࡞ࡃሗ࿌ࡉ
ࢀ࡚࠸ࡿ (17, 19-22)ࠋࡋ࠿ࡋ࡞ࡀࡽࠊࢡ࢚ࢳ࢔ࣆࣥࡸ࢜ࣛࣥࢨࣆࣥ࡞࡝ࡢ MARTA ࡣ௚ࡢᢠ⢭⚄
⑓⸆ࡼࡾࡶ⾑⢾್␗ᖖࡢⓎ⑕㢖ᗘࡀ㧗࠸ (23)ࠋ࢜ࣛࣥࢨࣆࣥ࡟ࡼࡿ㧗⾑⢾ࡢⓎ⑕ᶵᗎࡣᮍࡔ᫂ࡽ
࠿࡛࡞࠸ࠋ㐣ཤࡢ◊✲࡛ࠊ࢜ࣛࣥࢨࣆࣥࡢ཯᚟ᢞ୚ࡀ㣗ḧࡢஹ㐍ࡸయ㔜ቑຍࠊ⫧‶ࢆᘬࡁ㉳ࡇ
ࡋࠊ࢖ࣥࢫࣜࣥ᢬ᢠᛶࢆቑຍࡉࡏࡿࡇ࡜࡛ 2 ᆺ⢾ᒀ⑓ࢆច㉳ࡍࡿࡇ࡜ࡀ♧၀ࡉࢀ࡚࠸ࡿ (24-28)ࠋ
ᐇ㝿ࠊṚஸ౛ࢆྵࡴ㔜⠜࡞㧗⾑⢾⑕≧ࢆ࿊ࡋࡓᝈ⪅ࡢ⫼ᬒ࡟ࡣ⫧‶ࡸ⑕≧ࡢⓎ⌧┤๓ࡢ㐣㣗ࠊ⢾

2

Table 1. Classification of antipsychotic agents.
typical antipsychotic agent
phenothiazine derivatives

atypical antipsychotic agent
serotonin-dopamine antagonists (SDA)

Chlorpromazine

Risperidone

Levomepromazine

Perospirone

Perphenazine

Blonanserin

Fluphenazine

multi-acting receptor targeted antipsychotics
(MARTA)

Prochlorperazine

Clozapine

Trifluoperazine

Quetiapine

Propericiazine

Olanzapine

butyrophenone derivatives
Haloperidol

Asenapine
dopamine partial agonist

Spiperone

Aripiprazole

diphenylbutylpiperadine derivatives
Pimozide

benz amide derivatives
Sulpiride
Tiapride
Nemonapride
iminodibenzyl derivatives
Carpipramine
Clocapramine
Mosapramine
thiepine derivatives
Zotepine

ศࡢከ࠸Ύᾴ㣧ᩱỈࡢ኱㔞ᦤྲྀࡀሗ࿌ࡉࢀ࡚࠾ࡾࠊ㐣๫࡞⢾ࡢᦤྲྀ࡟ࡼࡾ࢖ࣥࢫࣜࣥࡢస⏝ࡸศ
Ἢࡢపୗࡀច㉳ࡉࢀࡓ࡜᥎ ࡉࢀ࡚࠸ࡿࠋ࢜ࣛࣥࢨࣆࣥ࡟ࡼࡿ㣗ḧࡢஹ㐍ࡸయ㔜ࡢቑຍࡢⓎ⑕ᶵ
ᗎ࡟ࡘ࠸࡚ࡣࠊ⬻ෆࡢ‶⭡୰ᯡ࡛⏕⌮ⓗ࡞㣗ḧࡢᢚไㄪ⠇࡟㛵୚ࡍࡿࣄࢫࢱ࣑ࣥ H1 ཷᐜయࢆ࢜ࣛ
ࣥࢨࣆࣥࡀ㐽᩿ࡍࡿࡇ࡜࡟⏤᮶ࡍࡿ࡜⪃࠼ࡽࢀ࡚࠸ࡿ (29) ࠋࡋ࠿ࡋ࡞ࡀࡽࠊ࢜ࣛࣥࢨࣆࣥ࡟ࡼࡾ

3

Table 2. Ki values of olanzapine against monoamine and acetylcholine muscarinic receptors (30).
receptor

Ki (nM)

receptor

Ki (nM)

D1

31

5-HT6

2.5

D2

11

5-HT7

104

D3

16

M1

1.9

D4

26

M2

18

D5

51

M3

25

5-HT1A

>1000

M4

13

5-HT1B

1355

M5

6

5-HT1D

800

α1

19

5-HT2A

2.5

α2

230

5-HT2B

11.8

β

>10000

5-HT2C

28.6

H1

7

5-HT3

57

GABAA

>10000

5-HT4

>1000

Benzodiazepine

>10000

ច㉳ࡉࢀࡿ㧗⾑⢾࡟ࡣయ㔜ࡢቑຍࢆకࢃ࡞࠸⑕౛ሗ࿌ࡶ࠶ࡿࡇ࡜࠿ࡽ (31-33)ࠊ㧗⾑⢾ࡢច㉳࡟ࡣ
H1 ཷᐜయࡢ㐽᩿స⏝࡟ࡼࡿ㣗ḧஹ㐍௨እࡢᶵᗎࡶ㛵୚ࡍࡿࡇ࡜ࡀ♧၀ࡉࢀ࡚࠸ࡿࠋ౛࠼ࡤࠊOzasa
ࡽࡣ࢜ࣛࣥࢨࣆࣥࡢ᭚㟢ࡀ࢖ࣥࢫࣜࣥࡢศἪࢆᢸ࠺⮅⮚ β ⣽⬊ࡢ࢔࣏ࢺ࣮ࢩࢫࢆㄏᑟࡍࡿࡇ࡜ࢆ
ሗ࿌ࡋ࡚࠸ࡿ (34)ࠋ௚࡟ࡶࠊ࢜ࣛࣥࢨࣆࣥࡢฎ⨨࡟ࡼࡾ⫢⮚࡛ࡢࢢࣝࢥ࣮ࢫ⏘⏕ࡀஹ㐍ࡉࢀࡿࡇ
࡜ࡸ (35, 36)ࠊᮎᲈ࡛ࡢࢢࣝࢥ࣮ࢫࢺࣛࣥࢫ࣏࣮ࢱ࣮ࢆ௓ࡋࡓ⣽⬊ෆ࡬ࡢ⢾ྲྀࡾ㎸ࡳࡀ㜼ᐖࡉࢀࡿ
ࡇ࡜ (37, 38)ࠊ࢔ࢻࣞࢼࣜࣥࡢศἪஹ㐍ࢆ௓ࡋࡓ㧗⾑⢾ࡢㄏⓎ࡞࡝ࡀሗ࿌ࡉࢀ࡚࠸ࡿ (39)ࠋ
ࣄࢺ࢖ࣥࢫࣜࣥࡣࠊ21 ಶࡢ࢔࣑ࣀ㓟࠿ࡽ࡞ࡿ࣌ࣉࢳࢻ A 㙐࡜ 30 ಶࡢ࢔࣑ࣀ㓟࠿ࡽ࡞ࡿ࣌ࣉ
ࢳࢻ B 㙐ࡀ஧ࡘࡢ S-S ⤖ྜ࡛㐃⤖ࡋࡓ࡛࣍ࣝࣔࣥ࠶ࡿ (Fig. 2)ࠋ⮅ β ⣽⬊࡟࠾࠸࡚ࠊ࢖ࣥࢫࣜࣥࡢ
ࡶ࡜࡜࡞ࡿ 110 ಶࡢ࢔࣑ࣀ㓟࠿ࡽ࡞ࡿࣉࣞࣉࣟ࢖ࣥࢫࣜࣥࡣ 24 ಶࡢ࢔࣑ࣀ㓟࠿ࡽ࡞ࡿࢩࢢࢼࣝ࣌

Fig. 2. Structure of human insulin.

4

ࣉࢳࢻࡀษ᩿ࡉࢀࠊࣇ࢛࣮ࣝࢹ࢕ࣥࢢࢆཷࡅࡿࡇ࡜࡛ࣉࣟ࢖ࣥࢫࣜࣥ࡟࡞ࡿࠋࣉࣟ࢖ࣥࢫࣜࣥࡣ
ࡉࡽ࡟ࣉࣟ࣍ࣝࣔࣥኚ᥮㓝⣲ (PC2 ࠾ࡼࡧ PC3) (40, 41)࡜࢝ࣝ࣎࢟ࢩ࣌ࣉࢳࢲ࣮ࢮ H (42) ࡢάᛶ࡟
ࡼࡾࣉࣟࢭࢩࣥࢢࢆཷࡅ࡚ࠊ࢖ࣥࢫࣜࣥ࡜ C ࣌ࣉࢳࢻ࡜࡞ࡾࠊ࡜ࡶ࡟ศἪ㢛⢏୰࡟㈓ⶶࡉࢀࡿࠋ
ࢢࣝࢥ࣮ࢫᏑᅾୗ࡟࠾ࡅࡿ࢖ࣥࢫࣜࣥศἪࡢ࣓࢝ࢽࢬ࣒࡟ࡘ࠸࡚ࡣ Fig. 3 ࡢࡼ࠺࡞⤒㊰ࡀ⪃࠼ࡽࢀ
࡚࠸ࡿࠋࡍ࡞ࢃࡕࠊ⾑୰ࡢࢢࣝࢥ࣮ࢫࡀୖ᪼ࡍࡿ࡜ࠊࢢࣝࢥ࣮ࢫ㍺㏦ᢸయ (GLUT) ࢆ௓ࡋࡓಁ㐍
ᣑᩓ࡟ࡼࡾ β ⣽⬊ෆ࡟ࢢࣝࢥ࣮ࢫࡀྲྀࡾ㎸ࡲࢀࡿ (43-45)ࠋྲྀࡾ㎸ࡲࢀࡓࢢࣝࢥ࣮ࢫࡣࠊゎ⢾⣔ࡢ
ᚊ㏿㓝⣲࡛࠶ࡿࢢࣝࢥ࢟ࢼ࣮ࢮ࡟ࡼࡾࢢࣝࢥ࣮ࢫ 6-ࣜࣥ㓟 (G6P) ࡟௦ㅰࡉࢀࡿ (46)ࠋ⏕ᡂࡋࡓ
G6P ࡣゎ⢾⣔࡛ࡉࡽ࡟௦ㅰࡉࢀࡿࡀࠊࡇࡢ㐣⛬࡟࠾࠸࡚ ATP ࡀ⏘⏕ࡉࢀࠊ⣽⬊ෆ ATP/ADP ẚࡀ
ୖ᪼ࡍࡿࡇ࡜࡛ ATP ឤཷᛶ K+ (KATP) ࢳࣕࢿࣝࡀ㛢ཱྀࡋࠊ⣽⬊⭷ࡀ⬺ศᴟࡍࡿࠋKATP ࢳࣕࢿࣝ㛢
ཱྀ࡟ࡼࡿ⣽⬊⭷ࡢ⬺ศᴟ࡟ࡼࡾ⭷㟁఩ࡀ L ᆺ㟁఩౫Ꮡᛶ Ca2+ࢳࣕࢿࣝ (L-type voltage-dependent
Ca2+ channel, L-type VDCC) ࡢ㜈⭷㟁఩ࡲ࡛㐩ࡍࡿ࡜ L-type VDCC ࡀάᛶ໬ࡉࢀࠊ⣽⬊እࡢ Ca2+ࡀ
ὶධࡍࡿࠋࡑࡢᚋࠊᑠ⬊య࠿ࡽࡢ Ca2+ᨺฟࡀ⥆ࡁࠊCa2+⃰ᗘࡢୖ᪼࡟ࡼࡾ࢖ࣥࢫࣜࣥศἪ㢛⢏ࡣ
⣽⬊⭷࡬ࢺࣛࣥࢫࣟࢣ࣮ࢺࡋࠊ࢖ࣥࢫࣜࣥࡣ࢚࢟ࢯࢧ࢖ࢺ࣮ࢩࢫ࡟ࡼࡾ㛤ཱྀศἪࡉࢀࡿ (47)ࠋ

Fig. 3. Mechanism of physiological insulin secretion from pancreatic β-cell.

5

࢔ࢻࣞࢼࣜࣥࡸ࢔ࢭࢳࣝࢥࣜࣥ࡞࡝ࡢ⚄⤒ఏ㐩≀㉁ࠊࢢࣝ࢝ࢦࣥᵝ࣌ࣉࢳࢻ (GLP-1) ࡞࡝ࡢ
࢖ࣥࢡࣞࢳࣥࡣ࢝ࣝࢩ࣒࢘ࢩࢢࢼࣝࢆ௓ࡋࡓ࢖ࣥࢫࣜࣥศἪࢆஹ㐍ࡉࡏࡿࡇ࡜ࡀ▱ࡽࢀ࡚࠸ࡿ
(48)ࠋ౛࠼ࡤࠊ࢔ࢻࣞࢼࣜࣥࡸࣀࣝ࢔ࢻࣞࢼࣜࣥࡣ⮅ β ⣽⬊ࡢ࢔ࢻࣞࢼࣜࣥ α2 ཷᐜయࢆ่⃭ࡍࡿ
ࡇ࡜࡛࢖ࣥࢫࣜࣥศἪࢆᢚไࡋ (49, 50)ࠊβ2 ཷᐜయࢆ่⃭ࡍࡿࡇ࡜࡛ศἪࢆಁ㐍ࡍࡿ (51)ࠋࡲࡓࠊ
࢔ࢭࢳࣝࢥࣜࣥࡣ࣒ࢫ࢝ࣜࣥᛶ࢔ࢭࢳࣝࢥࣜࣥ M3 ཷᐜయࢆ่⃭ࡍࡿࡇ࡜࡛࢖ࣥࢫࣜࣥศἪࢆஹ㐍
ࡍࡿ (52)ࠋࡉࡽ࡟ࠊGLP-1 ࡸᾘ໬⟶ᢚไ࣌ࣉࢳࢻ (GIP) ࡣࢢࣝࢥ࣮ࢫ่⃭ୗ࡛ྛཷᐜయࢆ่⃭ࡍࡿ
ࡇ࡜࡟ࡼࡾ࢖ࣥࢫࣜࣥࡢศἪࢆಁ㐍ࡍࡿ (53, 54)ࠋࡇࢀࡽࡢሗ࿌ࡣࠊ⮅ β ⣽⬊࠿ࡽࡢ࢖ࣥࢫࣜࣥศ
Ἢࡢㄪ⠇࡟⮅ β ⣽⬊࡟Ⓨ⌧ࡍࡿࣔࣀ࢔࣑ࣥࡸ࢔ࢭࢳࣝࢥࣜࣥࠊ࢖ࣥࢡࣞࢳࣥ࡞࡝ࡢཷᐜయࡀ┤᥋
㛵୚ࡍࡿࡇ࡜ࢆ♧၀ࡍࡿࡶࡢ࡛࠶ࡿࠋ࢜ࣛࣥࢨࣆࣥࡣ✀ࠎࡢࣔࣀ࢔࣑ࣥཷᐜయ࡟ᑐࡋ࡚ᣕᢠస⏝
ࢆ♧ࡍࡇ࡜࠿ࡽࠊ࢜ࣛࣥࢨࣆࣥࡀ⮅ β ⣽⬊࡟࠾ࡅࡿࣔࣀ࢔࣑ࣥཷᐜయࡢ㐽᩿స⏝ࢆ௓ࡍࡿࡇ࡜࡛
࢖ࣥࢫࣜࣥศἪࢆᢚไࡋࠊ㧗⾑⢾⑕≧ࢆច㉳ࡍࡿྍ⬟ᛶࡀ᥎ᐹࡉࢀࡿࠋࡋ࠿ࡋ࡞ࡀࡽࠊ⮅ β ⣽⬊
࠿ࡽࡢ࢖ࣥࢫࣜࣥศἪ࡟࠾ࡅࡿ࢔ࢻࣞࢼࣜࣥཷᐜయ௨እࡢࣔࣀ࢔࣑ࣥཷᐜయࡢ㛵୚࡟ࡘ࠸࡚ࡣ᫂
ࡽ࠿࡛࡞࠸ࠋᮏ◊✲࡛ࡣࠊࣁ࣒ࢫࢱ࣮⏤᮶⮅ β ⣽⬊ᰴ࡛࠶ࡿ HIT-T15 ⣽⬊ࢆ⏝࠸࡚ࠊ⮅ β ⣽⬊࠿
ࡽࡢ࢖ࣥࢫࣜࣥศἪ࡟࠾ࡅࡿࢻࣃ࣑ࣥࠊࢭࣟࢺࢽࣥ࠾ࡼࡧࣄࢫࢱ࣑ࣥཷᐜయࡢ㛵୚ࢆゎ᫂ࡍࡿࡇ
࡜ࢆ┠ⓗ࡜ࡋࡓࠋ

6

ᮏㄽ
1. ࣁ࣒ࢫࢱ࣮⏤᮶⮅ ș ⣽⬊ᰴ (HIT-T15) ⣽⬊࡟࠾ࡅࡿྛࣔࣀ࢔࣑ࣥཷᐜయࡢⓎ⌧ゎᯒ

1-1. ┠ⓗ
ᮏ◊✲࡛౑⏝ࡋࡓ HIT-T15 ⣽⬊ࡣࠊSyrian hamster (Mesocricetus auratus) ࡢ⮅ࣛࣥࢤࣝࣁࣥࢫ
ᓥ⣽⬊ࢆ simian virus 40 ࡛ࢺࣛࣥࢫࣇ࢛࣮࣒ࡍࡿࡇ࡜࡟ࡼࡾᶞ❧ࡋࡓ࢖ࣥࢫࣜࣀ࣮࣐⣽⬊ᰴ࡛࠶ࡿ
(55)ࠋHIT ⣽⬊࡟ࡣ࠸ࡃࡘ࠿ࡢࢧࣈࢡ࣮ࣟࣥࡀᏑᅾࡍࡿࡀࠊࡑࡢ୰࡛ࡶ HIT-T15 ⣽⬊ࡣ࢖ࣥࢫࣜࣥ
ྵ᭷㔞ࡀከࡃࠊࢢࣝࢥ࣮ࢫ⃰ᗘ౫Ꮡⓗ࡞࢖ࣥࢫࣜࣥศἪస⏝ࡔࡅ࡛࡞ࡃࠊࢢࣝ࢝ࢦࣥࡸࢫࣝ࣍ࢽ
ࣝᒀ⣲⸆࡟ࡼࡿ࢖ࣥࢫࣜࣥศἪࡢஹ㐍ࡸࢯ࣐ࢺࢫࢱࢳࣥ࡟ࡼࡿศἪࡢᢚไࡀሗ࿌ࡉࢀ࡚࠸ࡿ (5658)ࠋࡲࡓࠊṇᖖࡢ⮅ᓥ࡜ྠᵝ࡟ HIT-T15 ⣽⬊ෆࡢ cAMP ⃰ᗘ࡜⣽⬊እࡢ K+⃰ᗘࡢቑຍࡣ࢖ࣥࢫࣜ
ࣥࡢศἪࢆஹ㐍ࡍࡿ (56)ࠋࡇࡢࡼ࠺࡞⌮⏤࠿ࡽࠊHIT-T15 ⣽⬊ࡣከࡃࡢ࢖ࣥࢫࣜࣥศἪᐇ㦂࡟⏝࠸
ࡽࢀ࡚࠸ࡿࠋ
 ⮅ᓥࡸ⮅ β ⣽⬊࡟࠾ࡅࡿࣔࣀ࢔࣑ࣥཷᐜయࡢⓎ⌧࡟ࡘ࠸࡚ࡣࠊ࠸ࡃࡘ࠿ࡢሗ࿌ࡀ࠶ࡿࠋ౛࠼
ࡤࠊࣛࢵࢺ⮅ᓥ࡟ࢻࣃ࣑ࣥ D2, D3 ࠾ࡼࡧ D4 ཷᐜయࡀⓎ⌧ࡋ࡚࠸ࡿࡇ࡜ (59-61)ࠊ࣐࢘ࢫ⮅ᓥ࡟ D2,
D3 ཷᐜయ (61) ࠾ࡼࡧࢭࣟࢺࢽࣥ 5-HT2C ཷᐜయࡀⓎ⌧ࡋ࡚࠸ࡿࡇ࡜ (62)ࠊࣛࢵࢺ⏤᮶⮅ β ⣽⬊ᰴ࡛
࠶ࡿ INS-1 ⣽⬊࡟ D2, D3 ཷᐜయ (59, 63) ࠾ࡼࡧ 5-HT2B ཷᐜయࡀⓎ⌧ࡋ࡚࠸ࡿࡇ࡜ (64)ࠊ࣐࢘ࢫ⏤᮶
⮅ β ⣽⬊ᰴ࡛࠶ࡿ MIN6 ⣽⬊࡟ D2 ཷᐜయ (61)ࠊ5-HT2B ཷᐜయࡀⓎ⌧ࡋ࡚࠸ࡿࡇ࡜ (65) ࡀሗ࿌ࡉࢀ
࡚࠸ࡿࠋ୍᪉ࠊᮏ◊✲࡛౑⏝ࡋࡓ HIT-T15 ⣽⬊࡟࠾࠸࡚ࡣࠊࡇࢀࡽࡢࣔࣀ࢔࣑ࣥཷᐜయࡢⓎ⌧࡟
㛵ࡍࡿሗ࿌ࡣ࡞࠸ࠋࡑࡇ࡛ࠊ࢜ࣛࣥࢨࣆࣥࡢ୺せ࡞స⏝㒊఩࡛࠶ࡿࣔࣀ࢔࣑ࣥཷᐜయࡢ mRNA Ⓨ
⌧ࡀ HIT-T15 ⣽⬊࡛☜ㄆ࡛ࡁࡿ࠿ྰ࠿ࢆ RT-PCR ἲ࡛☜ㄆࡋࡓࠋࡉࡽ࡟ࠊ≉␗ⓗ࡞ᢠయࡀධᡭ࡛
ࡁࡓࢻࣃ࣑ࣥ D2 ࠾ࡼࡧࢭࣟࢺࢽࣥ 5-HT2A ཷᐜయ࡟㛵ࡋ࡚ࡣࠊࢱࣥࣃࢡ㉁ࡢⓎ⌧ࢆ western blot ἲ
࡛ゎᯒࡋࡓᇭ

1-2. ⤖ᯝ
ྛࣔࣀ࢔࣑ࣥཷᐜయ࡟ᑐࡍࡿ≉␗ⓗ࡞ࣉࣛ࢖࣐࣮ࢆタィࡋࠊRT-PCR ࡛ cDNA ࢆቑᖜࡋࡓᚋࠊ
2%࢔࣮࢞ࣟࢫࢤ࡛ࣝ㟁ẼὋືࢆ⾜ࡗࡓࠋࡑࡢ⤖ᯝࠊD2 ཷᐜయ࠾ࡼࡧࣄࢫࢱ࣑ࣥ H1 ཷᐜయ࡟ࡘ࠸
࡚┠ⓗ㛗ࡢࣂࣥࢻࡀ᳨ฟࡉࢀࡓࡀࠊࡑࡢ௚ࡢཷᐜయࡢⓎ⌧ࡣ☜ㄆ࡛ࡁ࡞࠿ࡗࡓࠋࡑࡇ࡛ࠊⓎ⌧ࡀ
☜ㄆ࡛ࡁ࡞࠿ࡗࡓ D3, D4 ཷᐜయࡸ 5-HT2A, 5-HT2B, 5-HT2C ࠾ࡼࡧ 5-HT6 ཷᐜయࠊH2 ཷᐜయ࡟ᑐࡋ࡚
2 ẁ㝵 PCR ࢆ⾜ࡗࡓࠋࡑࡢ⤖ᯝࠊ඲࡚ࡢཷᐜయ࡟ࡘ࠸࡚ mRNA ࡢⓎ⌧ࡀ☜ㄆ࡛ࡁࡓ (Fig. 4)ࠋࡉࡽ
࡟ࠊD2 ࠾ࡼࡧ 5-HT2A ཷᐜయࢱࣥࣃࢡ㉁ࡢⓎ⌧ࢆ western blot ἲ࡛ゎᯒࡋࡓ⤖ᯝࠊ࣌ࣉࢳࢻ-N-ࢢࣝ
ࢥࢩࢲ࣮ࢮ  (PNGase) ฎ⌮ᚋࡢ࣍ࣔࢪࢿ࣮ࢺ୰࡛ࡑࢀࡒࢀࡢཷᐜయࡢศᏊ㔞࡟┦ᙜࡍࡿ⣙ 60 kDa
࠾ࡼࡧ⣙ 48 kDa ࡟ࣂࣥࢻࡀ☜ㄆ࡛ࡁࡓ (Fig. 5)ࠋ

7

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