Design, synthesis, and BK channel-opening activity of hexahydrodibenzazepinone derivatives.
In order to explore new scaffolds for large-conductance Ca2+ -activated K+ channel (BK channel) openers, we carried out molecular design and synthesis on the basis of the following two concepts: (1) introduction of a heteroatom into the dehydroabietic acid (BK channel opener) skeleton would allow easier introduction of substituents. (2) Because of the fourfold symmetrical structure of BK channels, dimeric compounds in which two pharmacophores are linked through a tether are expected to have a greater binding probability to the channels, resulting in increased channel-opening activity. Herein, we explore the usefulness of the hexahydrodibenzazepinone structure as a new scaffold for BK channel openers. The synthesized monomer compounds of hexahydrodibenzazepinone derivatives, which can be derived from dehydroabietic acid, were subjected to electrophysiological patch-clamp studies, followed by Magnus contraction-relaxation assay using rabbit urinary bladder smooth muscle strips to assess overall activities. Dimeric compounds were designed by linking the monomeric hexahydrodibenzazepinone derivatives through a diacetylenebenzene tether, and their channel-opening activities were evaluated by electrophysiological methods. Finally, we concluded that the critical structure for BK channel-opening activity is the hexahydrodibenzazepinone monomer substituted with a phenyl-bearing alkynyl substituent on the lactam amide.
Tashima
Toshihiko
T
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Laboratory of Organic and Medicinal Chemistry, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Toriumi
Yoshimi
Y
Mochizuki
Yumi
Y
Nonomura
Taro
T
Nagaoka
Satoru
S
Furukawa
Katsuo
K
Tsuru
Hiromichi
H
Adachi-Akahane
Satomi
S
Ohwada
Tomohiko
T
D045784:Abietanes / Q000737:chemistry; D000818:Animals; D001552:Benzazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D003432:Cross-Linking Reagents; D019281:Dimerization; D015195:Drug Design; D004594:Electrophysiology; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000819:agonists* / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects; D011817:Rabbits; D001743:Urinary Bladder
D045784:Abietanes; D001552:Benzazepines; D003432:Cross-Linking Reagents; D051036:Large-Conductance Calcium-Activated Potassium Channels; C013913:dehydroabietic acid