Sensing G-Protein-Coupled Receptor 39 (GPR39) - ACS Publications

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Article

Model-based Discovery of Synthetic Agonists for the Zn 10

R1

0.46

10

log(EC50) (comp. alone)

b

-4 -5 -6 -7 26 (TM-N1562)

-8 -9

-8

-7

-6

-5

log [EC50] + 10 µM Zn2+

Similarity frequency

c

Similarity profile against 1.25 mill. ChEMBL comp. 106

8 26

105 104 103 102 101 0.1

0.3

0.5

0.7

0.9

Similarity Tanimoto Coef. [Bin]

d maximum cAMP act. maximum IP act. induced by Zn (%) induced by Zn (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

250 200 150 100 50 0

IP

100

cAMP

IP 10 µM Zn 2+

10 µM Zn 2+ no Zn

no Zn

2+

cAMP 3 µM Zn

50

2+

no Zn

2+

2+

3 µM Zn

2+ no Zn

2+

0 0 -10 -9 -8 -7 -6 -5

0 -10 -9 -8 -7 -6 -5

log [comp. 8] (M)

log [comp. 26] (M)

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Page 39 of 41

Insulin (pM per islet per min)

Figure 5 2000

a.

b.

1500 1000 500 0

Veh

Insulin (pM per islet per min)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

2000

c.

comp. 7

Veh

comp. 7

Veh

comp. 8

d.

1500 1000 500 0

Veh

comp. 8 GPR39 +/+

GPR39 -/-

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Journal of Medicinal Chemistry

Figure 6

Ghrelin secretion 400

% of basal ghrelin secretion

b

GPR39 +/+

***

350

** ** ** **

100

100 50

50

0

0 vehicle Iso

Zn

8

+Zn

26

26

8

+Zn

+Zn

vehicle Iso

+Zn

eI

GPR39 +/+

400

26

Zn

26

400 200 0

26

*

600

+Zn

GPR39 GPR39 +/+ -/-

+ Somatostatin antagonists

Somatostatin secretion

% of basal somatostatin secretion

*

150

*

Plasma Ghrelin

800

200

300 150

d

c

GPR39 -/-

250

Plasma Ghrelin (pg/ml)

a

GPR39 -/-

400

*

300

300

** ** **

200

** **

g proposed

200

mode of action GPR39 agonist

100

100

0 vehicle CGRP Zn

0 vehicle CGRP Zn

8

+Zn

26

26

+Zn

8

+Zn

26

Gq

+Zn

GPR39

IP signaling max IP response (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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f 150 100

dose-response curves on primary gastric cultures comp. 8

comp. 26

+ Zn

+ Zn

Somatostatin

50 0 0

-9

-8

-7

-6

-5

0

D-Cell

(somatostatin) Stomach

-9

-8

-7

-6

-5

log [compound] (M)

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Ghrelin Cell SSTR Gi

Ghrelin

Page 41 of 41

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

Table of Contents graphic

Library 1 Knowledge-based drug discovery approach Virtual screening of commercially available compounds based on SAR

Library 2

GPR39 activation discovery of novel biology

Library 3 Library 4 in vitro testing (using Zn2+ as a positive allosteric modulator)

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somatostatin secretion

ghrelin secretion