21th century drugs. “Magic bullet” or “ Multitarget warhead”

S.B.SeredeninState Zakusov Institute of Pharmacology RAMS, Moscow

State Zakusov Institute of Pharmacology RAMS, Moscow

Paul Ehrlich (1854-1915)The Nobel Prize in Physiology or Medicine 1908"in recognition of their work on immunityThe Ilya Ilyich Mechnikov1/2 of the prizeRussia Institut Pasteur Paris, France

Paul Ehrlich1/2 of the prizeGermanyGoettingen University Goettingen, Germany; Knigliches Institut fr experimentelle Therapie (Royal Institute for Experimental Therapy) Frankfurt-on-the-Main, Germany

Afobazol : -000861 03.11.2005State Zakusov Institute of Pharmacology RAMS, Moscow


Effect of emotional stress on the 3H-diazepam binding level in the brain membranes of MR & MNRA rats

Balb/cC57Bl/6Effect of emotional stress on the 3H-diazepam binding level in the brain membranes of Balb/c & C57Bl/6 miceMRMNRA* -

Effect of Afobazol on 3H-diazepam binding level in the brain membranes of Balb/c & C57Bl/6 miceEffect of Afobazol on 3H-diazepam binding level in the brain membranes of MR & MNRA ratsBalb/cC57Bl/6**MRMNRA** -

(CEREP, France)

1, A2A, A2B, A31, 2, 1, 2, 3 ( )BZDD1, D2S, D2L, D3, D4, D5 (- )GABAA, GABAB (1b) AMPA, Kainate, NMDA, Glycine (-), PCPH1, H2, H3, H4LPA1 (Edg-2)MT1, MT2, MT3 (ML2)M1, M2, M3, M4, M54 -BGTX- (42), 7 -BGTX-P2X, P2Yc5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT4e, 5-ht5A, 5-HT6, 5-HT7 1, 2

(CEREP, France)

AT1, AT2CCK1, CCK2 CRF1GAL1, GAL2NK1, NK2, NK3 YY1, Y2 , NTS1 , 2 (Delta opioid receptor), (Mu opioid receptor) (sst )V1a, V1b, V2

(CEREP, France)

GRPR -(R)-- Ca2+ CaV1.1 (L-) K+ KIR6 (KATP) Cl- NBTI (NET)BTCP (DAT) (GAT) (CHT) (SERT)

CalmodulinK+IP3CaM-PKCell EffectsIP3CaCaCaCaIP3PIP2PLC

Voltage-gated Ca channelNMDA RCa + +Ca + + receptorIP3 receptorLipid raftCa ATPaseCa + +AnkyrinBiPDHEAK+ channelIP3RState Zakusov Institute of Pharmacology RAMS, Moscow


[Melatonin]Cl-Cl-AfobazolGABA A R MT1 R3H-diazepam biding3H-diazepam biding- Melatonin- AfobazolState Zakusov Institute of Pharmacology RAMS, Moscow


Control (Localization on endoplasmatic reticulum)

Afobazol (10-8) (Localization on plasma membrane in 60 min following Afobazol application)

sigma-receptorsImmunofluorescence staining

CalnexinSigma-receptor + CalnexinState Zakusov Institute of Pharmacology RAMS, Moscow


Neuroprotective effect of Afobazol in HT-22 cell line exposed to oxidative stress

Application 24 h after H2O2Application 30 min before H2O2 Application right after H2O2Optical density Control 22 10-8 10-5 1,5 Optical density Control 22 10-8 10-5 1,5 Optical density Control 22 10-8 10-5 1,5 State Zakusov Institute of Pharmacology RAMS, Moscow


1

0.4890.0335062183

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0.02451168960.01910358450.00365759410.09421813880.000943633

10074.574028107.0406105.3169784.70802121.37014 , %

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survival (% of control)

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6.85194210.88444614.50983219.002174

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^

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0.03350621830.05322488970.07597861540.046228365

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6.85194210.88444615.5375489.453653275

2210-8 M10-5 M

1006.851942

74.57402810.884446

121.3701415.537548

84.708029.453653275

*

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22.80229420.8744928.14957429.99937..

^

H2O210-8 M10-5 M

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022.802294

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Protective effect of the Afobazol against glutamate toxicity in hippocampal cell culture HT-22 (MTT assay)

Controlglutamate5mM10-8 M

10-5 M24 h before glutamateAfter glutamateAfobazolControlglutamate5mM

11624hAfobazol (10-8 )Afobazol was able to prevent cell damage in concentrations which were defined in brain after systemic administration State Zakusov Institute of Pharmacology RAMS, Moscow


1

10023.249948

74.00204721.363358

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0.05678834970.05218031920.03092715460.0564033096

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MBD00162AB2.xls

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0.23866666670.18133333330.17818181820.16190909090.1967777778

0.02507322610.0388908730.04260473730.03495841690.0290033523.

0.00364291020.43305228450.12751771650.1768843201.

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MBD0016FBB3.xls

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Increase in Nerve growth factor (NGF) content 6 hours following Afobazol (10-8 ) application Western blot analysis 1 2 3 4 5 6 7 Control Afobazol NGF (10-8 ) NGFDensitometric units Densitometric analysis of the above Western blot ControlAfobazol*State Zakusov Institute of Pharmacology RAMS, Moscow


2

0.90.2645751311

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Concentration-dependent effect of Afobazol upon BDNF content in hippocampal cell line -2210-1110-710-610-510-1010-910-8CState Zakusov Institute of Pharmacology RAMS, Moscow


1

0.276342017

0.2613056476

0.3007634942

0.3156745706

0.3446396924

0.3205262568

0.334576634

0.3010756969

***

*

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BDNF/protein, pg/mkg

1

10-11 10-10 10-9 10-8 10-7 10-6 10-5

0.28041356850.25814378150.29212628790.34340854320.31461036590.3392783065

0.27735990490.29164450550.30475548040.28928109050.34587084160.33391917650.37506715740.2988965156

0.27125257770.30475548040.3192008250.28831751730.31569976950.3032548783

0.2524975920.30823939560.34377899470.3064367728

0.26040225720.32914288660.35168510820.32200522950.3653831154

0.24384010150.26556143460.30253125860.3055946822

0.2763420170.26130564760.30076349420.31567457060.34463969240.32052625680.3345766340.3010756969.

0.00466454820.01812378930.0210092230.02694782450.00174110790.02118164380.03032744250.0030818278.

Mean 1Mean 2pValid N1Valid N2Std.Dev.1Std.Dev.2

1 20.2763420170.3010756969

****Size of the brain infarct zone after the middle cerebral artery occlusion in rats Control 1,0 mg/kg 0,1 mg/kg 0,05 mg/kg AfobazolState Zakusov Institute of Pharmacology RAMS, Moscow


1

11.11.21.2

4.61.181.18

4.80.870.87

11.290.970.97

% infarct zone

1

1 /0,1 /0,05 /

12.144.913.5512.166.265.8911.14.64.811.29

0.981.130.772.011.261.161.21.180.870.97

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2

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MBD0015F6AE.xls

1

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Afobazol increase survival following the hemorrhagic stroke in ratsState Zakusov Institute of Pharmacology RAMS, Moscow


1

01700

01008

01100

02500

05008

*

#

insult + Afobazol (1,0)

sham-operated

insult

insult + Afobazol (0,1)

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% of the lost animals

1

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1

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2

3

Effect of Afobazol on the severity of neurological deficits in rats after hemorrhagic stroke (McGrows scale)

1 - Flabbiness, motor slowing2 weakness in extremities3 manege locomotion4 paresis of 1-4 extremitiesState Zakusov Institute of Pharmacology RAMS, Moscow


1

401006045

25904036

0401027

0401010

sham-operartedstrokestroke+afobazol (1,0)stroke+afobazol (0,1)

+ (1,0)

+ (0,1)

Symptoms

%

1

00000

1710112550

00000

08008

13714

1

*

#

+ (1,0)

+ (0,1)

%

2

402500

100904040

60401010

45362710

1 - ,

2 -

3 -

4 - 1-4

2

+ (1,0)

+ (0,1)

%

6

5

95696276

30261413

146105128110

97703925

13714

5

*

#

#

#

#

#

+ (1,0)

+ (0,1)

4

12482920

+ (1,0) + (0,1)

*

4

*

#

#

()

3

32241521

117129

21201715

33232337

13714

3

*

#

#

*

#

#

#

*

#

+ (1,0)

+ (0,1)

Ladasten : -010257/08State Zakusov Institute of Pharmacology RAMS, Moscow


(CEREP, France)

1, A2A, A2B, A31, 2, 1, 2, 3 ( )BZDD1, D2S, D2L, D3, D4, D5 (- )GABAA, GABAB (1b) AMPA, Kainate, NMDA, Glycine (-), PCPH1, H2, H3, H4LPA1 (Edg-2)MT1, MT2, MT3 (ML2)M1, M2, M3, M4, M54 -BGTX- (42), 7 -BGTX-P2X, P2Yc5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT4e, 5-ht5A, 5-HT6, 5-HT7 1, 2

(CEREP, France)

AT1, AT2CCK1, CCK2 CRF1GAL1, GAL2NK1, NK2, NK3 YY1, Y2 , NTS1 , 2 (Delta opioid receptor), (Mu opioid receptor) (sst )V1a, V1b, V2

(CEREP, France)

GRPR -(R)-- Ca2+ CaV1.1 (L-) K+ KIR6 (KATP) Cl- NBTI (NET)BTCP (DAT) (GAT)

Genes and proteins regulated by Ladastenaldolase A GAPDH Hsp70 CCTe VCP proteosoma 26S clathrin LCA tubulin alpha 6 alpha internexin CRMP-2 neuronal protein 22



1

2

2

2

5

glycolytic proteins

stress proteins

protection proteins

synaptic proteins

1

- 2

2

2

5

1

2

3

1

2

2

2

3

1

5

4

4

glycolytic gene

Ca signaling

Onco-suppressors

neuropeptides, extracellular secreted proteins

membrane transporter genes

synaptic function genes

neurogenesis

matrix adhesion receptors, cell-cell adhesion receptors, plasma membrane protein

1

2

2

2

3

1

5

4

4

1

2

3

Schematic rate of methylation 376 b.p. 5'-flanking region of tyrosinehydroxylase gene (-292 - +84) of rat brain hypothalamusLadastenControlState Zakusov Institute of Pharmacology RAMS, Moscow


1

0.90.8460.07276068750.0875429306

10.38500.1180166987

0.7270.2310.10804982510.1022220766

0.8180.4620.09358104380.1209170839

10.7500.1050210063

10.61500.1180166987

0.9090.5380.06975545520.1209170839

0.9170.9170.0669112670.066911267

10.84600.0875429306

10.93200.0610573501

1100

0.8330.4620.09045993590.1209170839

10.46200.1209170839

0.750.5380.10502100630.1209170839

0.9170.6920.0669112670.1119705844

10.84600.0875429306

0.9170.6670.0669112670.1143037748

CpG-nucleotides localisation

mean rate of methylation

%

19999

298100

39898

49899

598100

69699

710097

891100

995100

1095100

1198100

1210099

1398

97.166666666799.1538461538

. 2.55247948380.9870962336

1.44417468520.536581765

2.55247948382.5524794838

0.98709623360.9870962336

,

c.. .. (p)

-2690.90.072760687590.8460.0875429306110.9180120.90.846

-22810110.3850.118016698750.01581910.385

-2250.7270.108049825180.2310.102222076630.0716110.7270.231

-2180.8180.093581043890.4620.120917083960.2883830.8180.462

-15610120.750.105021006380.04844710.75

-14310110.6150.118016698780.19378910.615

-1400.9090.0697554552110.5380.120917083970.0928150.9090.538

-1340.9170.066911267110.9170.066911267111.0626090.9170.917

-11710120.8460.0875429306110.5210.846

-9510120.9320.0610573501121.0410.932

-8210121013211

-430.8330.0904599359100.4620.120917083960.1266930.8330.462

-1910120.4620.120917083960.0071410.462

-80.750.105021006390.5380.120917083970.4962710.750.538

150.9170.066911267110.6920.111970584490.3714290.9170.692

4910120.8460.0875429306110.5210.846

570.9170.066911267110.6670.114303774880.1937890.9170.667

double single sided

0.07276068750.07276068750.08754293060.0875429306

000.11801669870.1180166987

0.10804982510.10804982510.10222207660.1022220766

0.09358104380.09358104380.12091708390.1209170839

000.10502100630.1050210063

000.11801669870.1180166987

0.06975545520.06975545520.12091708390.1209170839

0.0669112670.0669112670.0669112670.066911267

000.08754293060.0875429306

000.06105735010.0610573501

0000

0.09045993590.09045993590.12091708390.1209170839

000.12091708390.1209170839

0.10502100630.10502100630.12091708390.1209170839

0.0669112670.0669112670.11197058440.1119705844

000.08754293060.0875429306

0.0669112670.0669112670.11430377480.1143037748

Ladasten inhibits GABA transporter gene expressionLADASTENhouse-keeping genetarget gene

Ladasten decrease the amount of IL-1 (CEREP, France)IL-1 hypersomnia

exhaustion

suppress appetite

decrease physical activity resistance

activation hypothalamus-hypophysis axis

increase catecholamines release depression like symptoms

decrease exploratory behavior



* +

Documents

21th century drugs. “Magic bullet” or “ Multitarget warhead”