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Page 1: New ligands of α2-adrenergic receptor with a potential anti-obesity activity

Joanna Śniecikowska, Monika Marcinkowska, Adam Bucki, Marcin Kołaczkowski, Maciej Pawłowski, Agata Siwek, Magdalena Dudek, Jacek Sapa

New ligands of α2-adrenergic receptor with a potential anti-obesity activity

Faculty of Pharmacy, Jagiellonian University Medical College, Cracow, Poland;

[email protected]

Obesity

Currently obesity is one of the top global health concerns. It is called a “disease of civilization“ of the 21st century.

According to the World Health Organization (WHO) 1.4 billion adults are overweight , and 200 million men and 300 million women are obese.

Obesity is suggested to be one of five leading risk factors for global mortality. Obese subjects are much more at risk for cardiovascular diseases, gastrointestinal tract diseases and different types of cancer.

Nevertheless, the therapeutic efficacy of current drugs remains limited and obesity present a serious unmet need.

General formula of the series targeting α2 receptor is presented below:

Adrenaline

AR-C239

Synthesis of novel arylpiperazine derivatives of tetrahydroisoquinoline-1,3-dione

Global obesity epidemic

Adrenaline and AR-C239 (selective α2-adrenergic receptor antagonist) in α2-adrenergic receptor

binding site

Structures and in vitro data for the tested compounds are collected in Table 1:

AR-C239 does not interact with Ser5.42, therefore showing antagonist properties.

Introduction of H-bond forming substituents to the phenyl moiety should provide agonist component to activity of this group of compounds.

Although α2 receptor antagonists seem to be significantly effective in the treatment of obesity their clinical utility as potential anti-obesity drugs because of their serious side effects.

Considering the fact, that introduction of some agonist component could allow to maintain therapeutic activity and at the same time decrease possible adverse effects, the synthesis of selective α2 receptor partial agonists, with low intrinsic activity was planned.

Compd A R % activity at α2 receptor

1.0E-05 M 1.0E-06 M 1.0E-07 M

1 79 50 100

2 1 51 100

3 3 93 100

4 1 74 71

5 1 36 69

6 4 85 78

7 17 100 100

8 2 24 69

9 1 51 100

AR-C239 1 10 80

Activity of novel tetrahydroisoquinolinedione derivatives

The highest activity was observed for compound A8 – a 2,2-dimethyl-1,3-benzodioxole derivative (below):

We designed and synthesized analogs of a reference α2 receptor antagonist AR-C239, variously substituted at the phenyl ring, to form H-bonds with Ser5.42

The synthetic methodology of 4,4-dimethylisoquinoline-1,3-(2H,4H)-dione derivatives was based on three retrosynthetic analyses.

Adrenaline forms H-bonds with Ser5.42, which contributes to its agonist effect.

As a result, synthetic route number II was selected.

Synthesis of the series was presented on the example of compound A8

Optimization of the synthetic route

No  Conditions % zawartość produktów   

 (A1 /by‐product G) in the reaction mixture  No  Conditions 

% zawartość produktów   

 (A1 /by‐product G) in the reaction mixture 

1 K2CO3, Et3N, 

KI, Acetonitrile 70°C /48h 

5 Et3N, KI 

DMF 

100°C/48h 

2 Et3N, KI 

Acetonitrile

Microwave/45min. 

6 K 2C O3, K I 

1,4-dioxane 

100°C / 72h 

3 K2CO3, KI 

DMF 

100°C/48h 

7 Et3N, KI 

1,4-dioxane 

100°C/48h 

4 Et3N, KI 

DMF 

100°C/48h 

8 K2CO3, KI 

1,4-dioxane 

50°C/24h 

0

20

40

60

A1 G

42,51%

5,56%

0

10

20

30

40

A1 G

31,12%

10,01%

0

20

40

60

80

A1 G

77,94%

9,02%

0

20

40

60

A1 G

59,37%

7,15%

0

5

10

15

A1 G

10,56%

3,07%

0

10

20

30

A1 G

11.52%

24,97%

0

10

20

30

A1 G

22,88%

8,23%

0

2

4

6

8

A1 G

7,28%

1,76%

Acknowledgements The studies were supported by National Centre of Science, grant no DEC-2011/03/B/NZ7/00635

The analysis of conditions used revealed that the end product is formed with the highest yield using dry 1,4-dioxan in the environment of anhydrous potassium carbonate and the presence of a stechiometric amount of potassium iodide at a temperature of 100 °C.

Based on the in vitro studies, this compound was selected for further pharmacological evaluation in animal models of obesity.

Asp3.32 Ser5.42

Asp3.32 Ser5.42