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J. Biol. Chem., Vol. 276, Issue 51, 47785-47793, December 21, 2001
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From the Crystallographic studies have elucidated the
binding mechanism of forskolin and P-site inhibitors to adenylyl
cyclase. Accordingly, computer-assisted drug design has enabled us to
identify isoform-selective regulators of adenylyl cyclase. After
examining more than 200 newly synthesized derivatives of forskolin, we
found that the modification at the positions of C6 and C7, in general,
enhances isoform selectivity. The 6-(3-dimethylaminopropionyl)
modification led to an enhanced selectivity for type V, whereas
6-[N-(2-isothiocyanatoethyl) aminocarbonyl] and
6-(4-acrylbutyryl) modification led to an enhanced selectivity for type
II. In contrast, 2'-deoxyadenosine 3'-monophosphate, a classical and
3'-phosphate-substituted P-site inhibitor, demonstrated a 27-fold
selectivity for inhibiting type V relative to type II, whereas
9-(tetrahydro-2-furyl) adenine, a ribose-substituted P-site ligand,
showed a markedly increased, 130-fold selectivity for inhibiting type
V. Consequently, on the basis of the pharmacophore analysis of
9-(tetrahydro-2-furyl) adenine and adenylyl cyclase, a novel
non-nucleoside inhibitor,
2-amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone (NKY80), was
identified after virtual screening of more than 850,000 compounds.
NKY80 demonstrated a 210-fold selectivity for inhibiting type V
relative to type II. More importantly, the combination of a type
III-selective forskolin derivative and 9-(tetrahydro-2-furyl) adenine
or NKY80 demonstrated a further enhanced selectivity for type III
stimulation over other isoforms. Our data suggest the feasibility of
adenylyl cyclase isoform-targeted regulation of cyclic AMP signaling by
pharmacological reagents, either alone or in combination.
Type-specific Regulation of Adenylyl Cyclase
SELECTIVE PHARMACOLOGICAL STIMULATION AND INHIBITION OF ADENYLYL
CYCLASE ISOFORMS*
§,,,,,, and
**
Research and Development Division,
Pharmaceuticals Group, Nippon Kayaku Co., Ltd., Tokyo 115-8588, Japan,
§ Departments of Physiology and Medicine, Yokohama City
University School of Medicine, Yokohama 236-0004, Japan, ¶ COR
Therapeutics Inc., South San Francisco, California 94080, and
Department of Medicine, Cardiovascular Research Institute,
University of Medicine and Dentistry of New Jersey,
Newark, New Jersey 07103
*
This study was supported in part by grants from the Japanese
Ministry of Education, Culture, Sports, Science, and Technology, the
Japanese Ministry of Health Labor and Welfare, and the Kitsuen Kagaku
Research Foundation, United States Public Health Service Grants HL38070
and HL54895, and American Heart Association Grant 9940187N.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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