This document describes research into new ligands for the α2-adrenergic receptor with potential anti-obesity effects. Researchers synthesized novel tetrahydroisoquinolinedione derivatives targeting the α2 receptor and tested their activity. The highest activity was found for compound A8, a 2,2-dimethyl-1,3-benzodioxole derivative. Optimization of the synthetic route found that the end product formed with the highest yield using dry 1,4-dioxane, potassium carbonate and potassium iodide at 100°C. Based on in vitro studies, compound A8 was selected for further evaluation in animal obesity models.

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
Faculty of Pharmacy, Jagiellonian University Medical College, Cracow, Poland;
joanna.gladysz@uj.edu.pl
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.
Activity of novel tetrahydroisoquinolinedione
derivatives
General formula of the series targeting α2 receptor is presented
below:
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.
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.
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
 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
K2C 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
60
40
20
0
A1 G
42,51%
5,56%
40
30
20
10
0
A1 G
31,12%
10,01%
80
60
40
20
0
A1 G
77,94%
9,02%
60
40
20
0
A1 G
59,37%
7,15%
15
10
5
0
A1 G
10,56%
3,07%
30
20
10
0
A1 G
11.52%
24,97%
30
20
10
0
A1 G
22,88%
8,23%
8
6
4
2
0
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