EM574 [Motilide] [Idremcinal]

Cat.# BLS0510

StructureOrigin: semi-synthetic from Erythromycin
CAS Registry Number: 110480-13-2

CH3HCHO 3O

H3CCH3O HON

CH3CA Index Name: 8,9-Didehydro-N-demethyl-9-deoxo6-deoxy-6,9-epoxy-N-(1methylethyl)-Erythromycin
Idremcinal

CHCH3 3O

HOAppearance: white powder

H3C

CH3CH3O

CH3O

O

O
O

CH3CH3OH

CH3

Molecular Formula/ Weight: C39H69NO12=743.98
Melting Point: 110-112℃ Purity: >97% by HPLC
Solubility:

Sol. in MeOH, DMSO, Chloroform,
EtOH, EtOAc, Acetone, Acetonitrile
Insoluble in water, Hexane

Background Information:
Motilides are a series of erythromycin derivatives (especially EM 522, EM 523, EM536 and EM 574) (Table 1)
1-4)
which showed gastrointestinal motor stimulating (GMS) activity without antibacterial activity . The GMS
activity is very similar to the effect caused by the hormone motilin (Fig. 1).
Motilides induce phase Ill-like contractions, which are similar to those induced by motilin, in the humangastrointestinal tract during the interdigestive state in dogs and humans. EM574 is a motilin receptor agonist
in the human gastric antrum in vitro, using contraction studies of muscle strips and isolated myocytes,
receptor binding assay and tissue section autoradiography. EM574 stimulated contractions of muscle strips ina concentration-dependent manner (10-7-10-5 M), and this contractile effect was unaffected by pretreatment
with atropine or tetrodotoxin. Isolated myocytes contracted in response to EM574 with a peak shortening at
10-7 M, which was comparable to the response to motilin5-10).
EM574 displaced specifically 125I-motilin bound to smooth muscle homogenates with a Kd value of 7.8 x 10-9M, compared with 4.5 x 10-9 M for motilin. Film autoradiograms showed that 125I-motilin-binding sites werelocalized in the muscle layers, and that the labeling disappeared in the presence of a 1,000 times molar
concentration of EM574. EM574 directly stimulates smooth muscle cell contraction by acting on motilin
receptors in the human gastric antrum in vitro 11) (Fig. 2).
We applied a rational computational procedure consisting of conformational analysis and a novel superposing
method to investigate the 3D structure-activity relationship between motilide (EM536) and motilin. The HA9,DA10, and DA11 atoms for EM536 were superposed on the DA9, HD10, and HD11 atoms for motilin,respectively. We have proposed common 3D structural features between these molecules, which may berelated to for their activity12) (Fig. 3).
Furthermore, EM574 has an orexigenic activity with affinity for growth-hormone secretagogue receptor (GSHR), which Ghrelin binds13).
Handling and Storage:
Store at -20℃.

References:
1. S. Ōmura et al., J. Antibiot., 38, 1631-1632 (1985).
2. S. Ōmura et al., J. Med. Chem., 30, 1941-1943 (1987).

()
3. K. Tsuzuki et al., Chem. Pharm. Bull., 37, 2687-2700 (1989).
4. T. Sunazuka et al., Chem. Pharm. Bull., 37, 2701-2709 (1989)
5. Z. Itoh et al., Chemotherapy, 36, 104-115 (1988)
6. N. Inatomi et al., J. Pharmacol. Exp. Ther., 251, 707-712 (1989)
7. S. Ōmura et al., In “Motilin” (Ed. By Z. Itoh) pp. 245-256,
Academic Press (1990)
8. T. Satoh et al., J. Pharmacol. Exp. Ther., 254, 940-944 (1990)
9. M. Satoh et al., J. Pharmacol. Exp. Ther., 271, 574-579 (1994)
10. N. Inatomi et al., In “MACROLIDE ANTIBIOTICS” (Ed. By S. Ōmura) pp.
501-531, Academic Press (2002)
11. Y. Kondo et al., Biochem. Biophys. Res. Commun., 150, 877-882 (1988)
12. H. Gouda et al., Chem. Pharm. Bull., 48, 1835-1837 (2000)
13. A. Asakawa et al., J. Gastroenterology and Hepatology, 18, 881-882 (2003)

Synthesized by Organic Chemistry Group, The Kitasato Institute.

Antibacterial Activity and Gastrointestinal Motor
Stimulating (GMS) Activity of Motilides
Antibacterial activity

CompoundGMS activity2)(MIC, µg/ml)1)

EM A

0.21

EM 2015010EM 523>10018

EM 574>100248

EM 536>10028901) Staphylococcus aureus ATCC 6538P, agar dilution method.
2) GMS activity was estimated by 2 X 2 points pallel line assay.
MeMeNO
9MeHO

MeMeHO 6Me HOO

MeOO

MeOOOHO6Me HOO

MeOH
Me

Erythromycin A (EM A)

O

9MeO

MeO

EM 201
EM 523
EM 574

OOHO6Me HOO

MeOH
MeR = MeR = Et
R = i-Pr

IMe+NMeO

MeMeHOOMeO

MeMeMeHOOMeO

MeMeMeHON

9MeMeR

MeO

MeOO

OMeO

EM 536MeOH
MeEM
574(30µg/Kg)
EM A(30µg/Kg)

Gastrointestinal
constraction induced
EMEM
A (30µg/Kg)
Gastrointestinal
Constraction
Inducedbyby
574 (30µg/Kg)

Displacement
Iodinated
Motilin
Bindingof Motilides
Displacement ofofiodinatedmotilinbindingof motilides

Hydrophobic (HP)
H-acceptor (HA)
H-donor (HD)HP1

EM 536 (Motilide)
HP4HOO
HA8

DA11 HO

HA9O

HP5O

DA10N
HA7 HOOO
HP2
HP3O

O HA6Motilin
HP1
HA7
HD10H O HP3 H+NN
H3NNO
O
HA6OOH

H-donor/acceptor (DA)HP2HA8HP4ONH

HOHP5HNOO
HODA9O—ON
H O
HD11HNONHO
HNO

NH2ONH

H
NOO
NH+

H2N

NH2

Three-dimensional Structure-activity Relationship Analysis between Motilin andMotilide Using Conformational Analysis and a Novel Molecular Superposing Method
H. Gouda et al., Chem.Pharm.Bull, 48,1835 (2000)