2-Alkynyl-8-aryladenines possessing an amide moiety: their synthesis and structure-activity relationships of effects on hepatic glucose production induced via agonism of the A(2B) adenosine receptor.
A series of 2-alkynyl-8-aryladenine derivatives bearing an amide moiety at the 9-position of adenine was synthesized. These analogues were evaluated for inhibitory activity on N-ethylcarboxamidoadenosine (NECA)-induced glucose production in primary cultured rat hepatocytes. The m-primary benzamide derivative 15f was the most potent compound (IC(50)=0.017 microM), being 15-fold more active than the corresponding 9-methyl derivative (1). Compound 15f showed 72- and 5.2-fold selectivity for human A(2B) receptor versus human A(1) and A(2A) receptors, respectively. Structure-activity relationship (SAR) studies of the synthesized compounds indicated that a three-carbon linker, fixed in the form of a benzene ring, between the adenine core and the amide moiety is important for both A(2B) antagonistic activity and selectivity. The IC(50) values in rat hepatocyte glucose assay correlated well with the IC(50) values in cAMP assay using Chinese hamster ovary cells stably transfected with human A(2B) receptors (r(2)=0.94). The A(1) and A(2A) affinities showed no correlation with the potency to inhibit NECA-induced glucose production. These results strongly support our previous conclusion that adenosine agonist-induced hepatic glucose production in rat hepatocytes is mediated through the A(2B) receptor.
Harada
H
H
Tsukuba Research Laboratories, Eisai Company, Ltd., 5-1-3 Tokodai, Tsukuba, 300-2635, Ibaraki, Japan. h-harada@hhc.eisai.co.jp
Asano
O
O
Kawata
T
T
Inoue
T
T
Horizoe
T
T
Yasuda
N
N
Nagata
K
K
Murakami
M
M
Nagaoka
J
J
Kobayashi
S
S
Tanaka
I
I
Abe
S
S
D000225:Adenine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000480:Alkynes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D006224:Cricetinae; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000096:biosynthesis*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D010053:Ovary / Q000166:cytology / Q000378:metabolism; D058906:Purinergic P1 Receptor Agonists; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection
C437743:3-(6-amino-8-(3-fluorophenyl)-2-(2-(1-hydroxycyclohexyl)-1-ethynyl)-9H-9-purinyl)benzamide; D000480:Alkynes; D001549:Benzamides; D007004:Hypoglycemic Agents; D058906:Purinergic P1 Receptor Agonists; D011687:Purines; D018047:Receptors, Purinergic P1; D005947:Glucose; D000225:Adenine