| Co-Investigator(Kenkyū-buntansha) |
TAKADA Tatsuyuki National Children's Medical Res. Center, Researcher, 小児医療研究センター・小児薬理研究部, 重点研究支援協力員
TAKEI Yoshinori National Children's Medical Res. Center, Researcher, 小児医療研究センター・小児薬理研究部, 重点研究支援協力員
HIRASAWA Akira National Children's Medical Res. Center, Researcher, 小児医療研究センター・小児薬理研究部, 研究員 (70242633)
ITO Shuji OTSUKA PHARMACEUTICAL CO., LTD., 2ND TOKUSHIMA INSTITUTION OF NEW DRUG RESEARCH, RESEARCHER, 徳島新薬第二研究所, 研究員
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| Research Abstract |
In the present study, we examined a new strategy for drug discovery based on the recent development in molecular biology. Recently, a number of G-protein coupled receptors (GPCR) have been cloned and are found to have a large gene family. Each GPCR has several subtypes and physiological function of the GPCR is mediated by these subtypes. We planed to clone all members of a certain GPCR in human by homology cloning method with PCR, and then construct cell lines stably expressing the cloned receptor, analyze the signal transduction, and as a final goal to discover a novel subtype receptor-specific drug by using the cells. Using alpha1-adrenoceptor (alpha1-AR) as a model, we examined this new strategy for drug discovery. We cloned three different human alpha1-AR subtypes (a, b and d-type), and obtained the cells stably expressing these three subtypes. All alpha1-AR s are found to be coupled to Gq/1 1 proteins and Ca2+ signaling. Utilizing these cell lines, we found that a novel alphal -AR antagonist KMD-3213 is very selective for alpha1 a-subtype, and can be very useful for the treatment of benign prostate hypertrophy without no untoward effect on the blood pressure. Furthermore, developing antibodies against alpha1 b-AR, we first succeeded in detecting the tissue localization of the alpha1 b-AR protein. Taken together, the present study clearly showed that molecular biological methodology can be potentially of use for drug discovery, targeted GPCR in particular.
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