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비만 억제 작용을 가진 세로토닌2C 수용체 효능제
Reports NRF is supported by Research Projects( 비만 억제 작용을 가진 세로토닌2C 수용체 효능제 | 2006 Year 신청요강 다운로드 PDF다운로드 | 천승훈(전남대학교) ) data is submitted to the NRF Project Results
Researcher who has been awarded a research grant by Humanities and Social Studies Support Program of NRF has to submit an end product within 6 months(* depend on the form of business)
  • Researchers have entered the information directly to the NRF of Korea research support system
Project Number E00161
Year(selected) 2006 Year
the present condition of Project 종료
State of proposition 재단승인
Completion Date 2008년 02월 25일
Year type 결과보고
Year(final report) 2008년
Research Summary
  • Korean
  • 비만은 경제적으로 풍족하여 음식이 풍부하며 생활환경이 개선되어 운동이 부족한 성인들에게 가장 많이 발병되어 큰 사회문제가 되고 있으며 당뇨, 고혈압, 고지혈증, 심장병, 뇌졸중, 각종 암 등을 유발 또는 악화시켜 사회ㆍ경제적으로 막대한 손실을 초래하고 있기 때문에 이러한 비만을 치료할 수 있는 약물을 개발하려는 연구가 세계에서 가장 활발히 진행되고 있습니다.

    전 세계적으로 다양한 표적을 이용하여 약물 개발에 노력한 결과 소화관에서 지방의 흡수를 억제하는 약물과 식욕억제제가 시판되고 있으나 부작용으로 인하여 장기간 사용할 수 없으므로 새로운 작용기전을 갖는 비만치료 약물 개발이 활발히 진행되고 있습니다. 비만치료제 개발의 새로운 표적으로 떠오르는 것들 중 최근에 주목을 받고 있는 비만치료제 개발의 표적은 세로토닌 입니다. 세로토닌 수용체는 활성화 되면 식욕억제, 체중감소 등의 효과를 나타냅니다.

    지금까지 알려진 세로토닌 수용체 효능제로써 식욕억제 효과를 나타내는 것으로 보고된 물질 중 하나는 피라지노퀴녹살린온으로 본 연구에서는 이 물질을 선도물질로 하고 구조-활성상관관계 연구를 통하여 더 좋은 효과를 나타내는 새로운 물질을 설계하고 합성하였습니다. 선도물질이 가지고 있는 락탐을 락톤으로 치환하여 염기성을 나타내는 질소원자의 수를 줄이고 수소결합을 더 강하게 할 수 있는 산소원자를 도입함으로써 수용체와의 결합력을 증가시킬 수 있을 거라는 가정에서 락톤 구조를 포함한 5개의 물질을 합성하고 효력을 측정하여 선도물질과 유사한 효력을 나타내나 선택성이 더 나은 물질을 발견하였습니다.
  • English
  • Obesity impairs overall quality of health and is known to be a major risk factor in the development of T2DM, osteoarthritis, hypertension, dyslipidemia, coronary artery disease, stroke, and certain cancers. The increasing prevalence of obesity in the developed and developing countries has prompted research community to discover treatments that reduce body weight.
    Currently, two drugs are approved for the long-term treatment of obesity, sibutramine and orlistat. Since these drugs have limited clinical efficacy, low tolerability and some sideeffects, there is room for improvements in the pharmacotherapies for the treatment of obesity.
    Many potential biological targets for treating obesity have recently emerged, including CB-1R, MCH1R, MC4R and 5-HT2C.
    Recently, pyrazinoquinoxalinones were reported as selective 5-HT2C receptor agonists and these compounds were selected as a lead. Quantitative structure-activity relationship studies of this lead compound led to a discovery of an active compound. Hypothesis was replacing one of the basic nitrogen atoms in the molecule with oxygen atom could increase 5-HT2C receptor binding affinity through better H-bonding. Among the compounds synthesized and tested, one exhibited better efficacy and selectivity than the lead compound.
Research result report
  • Abstract
  • Substituted 2,3,4,4a-tetrahydropyrazino[2,1-c][1,4]benzoxazin-5-(1H)-ones were synthesized and evaluated as 5-HT2C receptor agonists for the possible treatment of obesity. A number of compounds were shown to exhibit 5-HT2C agonist binding activity and compound 19 displayed the most potent in vitro activity.
  • Research result and Utilization method
  • In preclinical studies, it has been established that the 5-HT2C receptor subtype is involved in the regulation of appetite in animals through the use of 5-HT2C receptor agonists, antagonists, and transgenic mouse models. In clinical studies, the nonselective 5-HT2C receptor agonist, m-chlorophenylpiperazine (m-CPP, 5) was shown to decrease food intake and body weight of obese subjects. The main side-effects of hallucinogenesis and valvular hypertrophy are caused by the activation of 5-HT2A and 5-HT2B receptor, respectively. Recently, a series of pyrazinoquinoxalinones, exemplified by 7, were reported by Wyeth-Ayerst as potent and selective 5-HT2C agonists in in vitro and in vivo. Compound 7 is structurally similar to the known nonselective 5-HT2C agonist m-CPP (5). However, 7 was reported to exhibit 5-HT2C agonist binding and functional activity as well as in vivo activity tested using a rat feeding model. It was reasoned that converting quinoxalinone portion of 7 to benzoxazinone and maintaining only two basic nitrogen atoms of the piperazine ring of m-CPP (5) might produce new analogues with improved selectivity and oral potency.

    General synthetic route was developed for the preparation of 2,3,4,4a-tetrahydropyrazino[2,1-c][1,4]benzoxazin-5-(1H)-ones as outlined in Scheme 1. (o-Nitrophenyl)piperazine derivatives (8-12) were prepared in excellent yields by heating appropriately substituted o-nitrofluorobenzenes with 4-carbobenzyloxy-2-cyanopiperazine and triethylamine in N,N-dimethylforamide. Reduction of the substituted nitrophenyl to the aniline was accomplished in high yield using iron in acetic acid. Diazotization of the aniline compounds (13-17) followed by hydroxylation of the aryldiazonium salts afforded the phenol intermediates that lactonized under acidic conditions to give benzoxazinones directly. Apparently the phenol intermediates underwent intramolecular Pinner cyclization followed by hydrolysis to afford benzoxazinones under the reaction conditions. Incidentally the carbobenzyloxy-protecting group of the piperazine nitrogen was also hydrolyzed under the acidic reaction conditions to yield the desired products (18-22).

    All of the synthesized compounds (18-22) were tested for their 5-HT2C agonist and antagonist binding affinities and these results are presented in Table 1. From the binding data available, it can be generalized that all of the compounds tested displayed a higher selectivity for agonist binding over antagonist binding. Substitution at R1 and/or R2 increased agonist affinity (18 vs 19-22). Disubstitution at R1 and R2 has a pronounced effect on binding affinity compared to no substitution or monosubstitution at R1 and R2 (19 vs 18, 20-22). Monosubstitution at R1 (similar to m-CPP) gave a higher binding affinity (19, 21) than monosubstitution at R2 (20, 22). The most active and selective agonist was dichlorosubstitution at R1 and R2 (19). In general, 2,3,4,4a-tetrahydropyrazino[2,1-c][1,4]benzoxazin-5-(1H)-ones exhibited weaker agonist binding affinities compared to 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5-(6H)-ones.

    From this series, compound 19 emerged as a potent, selective 5-HT2C receptor agonist that could be used as an anoretics for the clinical treatment of obesity.
  • Index terms
  • 5HT2C receptor agonist, Pyrazinobenoxazinone, Anoretic
  • List of digital content of this reports
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