SELECTIVE SEROTONERGIC AGENTS
SELECTIVE SEROTONERGIC AGENTS
批准号:
6703087
负责人:
RICHARD A GLENNON
金额:
$25.95万
依托单位国家:
美国
项目类别:
财政年份:
2001
资助国家:
美国
项目状态:
已结题
起止时间:
2001-02-15 至 2006-01-31
中文摘要
描述(改编自申请人摘要):
5-羟色胺(5-hydroxytryptamine; 5-HT)受体与广泛的
各种神经精神疾病,包括精神分裂症,抑郁症,
焦虑、强迫行为和恐慌症。之多样
这些影响至少可以部分地由大量的
现已确定的5-HT受体群:5-HT 1 -5-HT 7。许多
这七个种群已被证明是由亚群组成的,
至少有20种不同的5-HT受体亚群和剪接变体,
被克隆了在某些情况下,这些5-HT群体的确切作用是
由于缺乏选择性血清素能配体,这仅仅是推测性的。的确,
很少有真正的亚群选择性激动剂或拮抗剂被
开发本研究的目的是开发此类制剂。
具体地,我们提出(a)解释5-HT 2A对5-HT 2C的选择性,
并开发和测试一个全面的模型,
允许从头设计和合成新的5-HT 2 A拮抗剂,(B),
利用5-HT 6选择性激动剂的第一个例子,和(c)探索
新发现的5-HT 1F配体。5-HT 2A拮抗剂可能具有非典型性
抗精神病药,有证据表明,5-HT 6受体可能参与
精神病,抑郁症和情绪障碍,初步研究结果表明,
5-HT 1F受体可能在偏头痛中起作用。尽管可能存在
在开发这种药物的临床价值方面,它们的确切用途还远不清楚
在这个时候因此,该应用程序更直接的目标是开发
这些药物作为工具,以进一步研究药理学意义,
这些受体群体和研究基本的神经化学机制。
我们在初步调查过程中已确定,(a)
5-HT 2A对5-HT 2C拮抗剂(即,KML-010),(B)5-HT 6选择性
激动剂(即,2-MMT),和(c)新型5-HT 1F配体。KML-010的新类似物
将合成并在放射性配体结合和行为研究中进行检查
为了测试我们制定的假设模型,
螺哌隆的5-HT 2A选择性和酮色林的缺乏选择性。的
5-HT 6激动剂2-MMT尚未得到彻底研究,仅与
亲和力中等,可能难以穿透血脑
这是由于其化学成分。我们建议系统地利用
我们已经确定的其他线索,以优化活动。
将进行放射性配体结合和功能测定。5-HT 1F配体
不是选择性的,我们建议探索其结构-活性关系
和功能活性,试图开发5-HT 1F-选择性配体。
英文摘要
DESCRIPTION(Adapted from applicant's abstract):
Serotonin (5-hydroxytryptamine; 5-HT) receptors have been implicated in a wide
variety of neuropsychiatric disorders including schizophrenia, depression,
anxiety, obsessive-compulsive behavior, and panic disorders. The diversity of
these implications can be explained, at least in part, by the large number of
5-HT receptor populations that now have been identified: 5-HT1-5-HT7. Many of
these seven populations have been shown to consist of subpopulations and at
least 20 different subpopulations and splice variants of 5-HT receptors have
been cloned. In some instances, the exact role(s) of these 5-HT populations is
merely speculative due to the lack of selective sertonergic ligands. Indeed,
very few truly subpopulation-selective agonists or antagonists have been
developed. The purpose of the present investigation is to develop such agents.
Specifically, we propose (a) to explain the 5-HT2A versus 5-HT2C selectivity of
spiperone and to develop and test a comprehensive model that might eventually
allow the de novo design and synthesis of novel 5-HT2A antagonists, (b) to
exploit the first example of a 5-HT6-selective agonist, and (c) to explore a
newly identified 5-HT1F ligand. 5-HT2A antagonists may be of value as atypical
antipsychotics, there is evidence that 5-HT6 receptors may be involved in
psychosis, depression, and mood disorders, and preliminary findings suggest
that 5-HT1F receptors may play a role in migraine. Although there may be
clinical value in developing such agents, their exact utility is far from clear
at this time. Hence, a more immediate goal of this application is to develop
such agents as tools to further investigate the pharmacologic significance of
these receptor populations and to study basic neurochemical mechanisms.
We have already identified in the course of our preliminary investigations, (a)
a 5-HT2A versus 5-HT2C antagonist (i.e., KML-010), (b) a 5-HT6-selective
agonist (i.e., 2-MMT), and (c) a novel 5-HT1F ligand. New analogs of KML-010
will be synthesized and examined in radioligand binding and behavioral studies
in order to test a hypothetical model we have formulated to account for the
5-HT2A selectivity of spiperone and the lack of selectivity of ketanserin. The
5-HT6 agonist 2-MMT has not been thoroughly investigated, binds only with
modest affinity, and likely will have difficulty in penetrating the blood-brain
barrier due to its chemical composition. We propose to systematically exploit
additional leads we have already identified in an attempt to optimize activity.
Radioligand binding and functional assays will be conducted. The 5-HT1F ligand
is not selective; we propose to explore its structure-activity relationships
and functional activity in an attempt to develop a 5-HT1F-selective ligand.
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Interaction of N1-unsubstituted and N1-benzenesulfonyltryptamines at h5-HT6 receptors.
N1-未取代和 N1-苯磺酰色胺在 h5-HT6 受体上的相互作用。
DOI:
10.1016/j.bmcl.2006.08.068
发表时间:
2006
期刊:
Bioorganic & medicinal chemistry letters
影响因子:
2.7
作者:
[Kolanos,Renata, Dukat,Malgorzata, Roth,BryanL, Glennon,RichardA]
通讯作者:
Glennon,RichardA
Possible differences in modes of agonist and antagonist binding at human 5-HT6 receptors.
人类 5-HT6 受体激动剂和拮抗剂结合模式可能存在差异。
DOI:
10.1016/j.bmcl.2004.05.076
发表时间:
2004
期刊:
Bioorganic & medicinal chemistry letters.
影响因子:
--
作者:
[Pullagurla,ManikR, Westkaemper,RichardB, Glennon,RichardA]
通讯作者:
Glennon,RichardA
DOI:
10.1021/jm060469q
发表时间:
2006-07
期刊:
Journal of medicinal chemistry
影响因子:
7.3
作者:
[D. Sikazwe;M. Bondarev;M. Dukat;J. B. Rangisetty;B. Roth;R. Glennon]
通讯作者:
D. Sikazwe;M. Bondarev;M. Dukat;J. B. Rangisetty;B. Roth;R. Glennon
1,2,3,4-tetrahydrocarbazoles as 5-HT6 serotonin receptor ligands.
1,2,3,4-四氢咔唑作为 5-HT6 血清素受体配体。
DOI:
10.1016/j.bmcl.2004.01.071
发表时间:
2004
期刊:
Bioorganic & medicinal chemistry letters.
影响因子:
--
作者:
[Chang-Fong,Jean, Rangisetty,JagadeeshB, Dukat,Malgorzata, Setola,Vincent, Raffay,Thomas, Roth,Bryan, Glennon,RichardA]
通讯作者:
Glennon,RichardA
N1-benzenesulfonylgramine and N1-benzenesulfonylskatole: novel 5-HT6 receptor ligand templates.
N1-苯磺酰麦胺和 N1-苯磺酰粪臭素:新型 5-HT6 受体配体模板。
DOI:
10.1016/s0960-894x(03)00612-7
发表时间:
2003
期刊:
Bioorganic & medicinal chemistry letters
影响因子:
2.7
作者:
[Pullagurla,ManikR, Dukat,Małgorzata, Setola,Vincent, Roth,Bryan, Glennon,RichardA]
通讯作者:
Glennon,RichardA
共 7 条
SELECTIVE SEROTONERGIC AGENTS
-
批准号:6629270
-
项目类别:
-
资助金额:$25.95万
-
财政年份:2001
-
负责人:RICHARD A GLENNON
-
依托单位:
SELECTIVE SEROTONERGIC AGENTS
-
批准号:6499357
-
项目类别:
-
资助金额:$25.95万
-
财政年份:2001
-
负责人:RICHARD A GLENNON
-
依托单位:
SELECTIVE SEROTONERGIC AGENTS
-
批准号:6266922
-
项目类别:
-
资助金额:$27.08万
-
财政年份:2001
-
负责人:RICHARD A GLENNON
-
依托单位:
SYNTHESIS OF NICOTINE ANALOGS
-
批准号:6358470
-
项目类别:
-
资助金额:$17.12万
-
财政年份:2000
-
负责人:RICHARD A GLENNON
-
依托单位:
SYNTHESIS OF NICOTINE ANALOGS
-
批准号:6218897
-
项目类别:
-
资助金额:$0.66万
-
财政年份:1999
-
负责人:RICHARD A GLENNON
-
依托单位:
SYNTHESIS OF NICOTINE ANALOGS
-
批准号:6103988
-
项目类别:
-
资助金额:$0.66万
-
财政年份:1999
-
负责人:RICHARD A GLENNON
-
依托单位:
SYNTHESIS OF NICOTINE ANALOGS
-
批准号:6269973
-
项目类别:
-
资助金额:$19.74万
-
财政年份:1998
-
负责人:RICHARD A GLENNON
-
依托单位:
SYNTHESIS OF NICOTINE ANALOGS
-
批准号:6237888
-
项目类别:
-
资助金额:$18.18万
-
财政年份:1997
-
负责人:RICHARD A GLENNON
-
依托单位:
B CARBOLINE HALLUCINOGENS
-
批准号:2122196
-
项目类别:
-
资助金额:$20.41万
-
财政年份:1996
-
负责人:RICHARD A GLENNON
-
依托单位:
B CARBOLINE HALLUCINOGENS
-
批准号:2897935
-
项目类别:
-
资助金额:$18.1万
-
财政年份:1996
-
负责人:RICHARD A GLENNON
-
依托单位:
B CARBOLINE HALLUCINOGENS
-
批准号:2700881
-
项目类别:
-
资助金额:$17.49万
-
财政年份:1996
-
负责人:RICHARD A GLENNON
-
依托单位:
B CARBOLINE HALLUCINOGENS
-
批准号:2414604
-
项目类别:
-
资助金额:$19.05万
-
财政年份:1996
-
负责人:RICHARD A GLENNON
-
依托单位:
SELECTIVE SIGMA LIGANDS: DESIGN SYNTHESIS & EVALUATION
-
批准号:3384907
-
项目类别:
-
资助金额:$16.77万
-
财政年份:1991
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负责人:RICHARD A GLENNON
-
依托单位:
SELECTIVE SIGMA LIGANDS: DESIGN SYNTHESIS & EVALUATION
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批准号:2246478
-
项目类别:
-
资助金额:$16.61万
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财政年份:1991
-
负责人:RICHARD A GLENNON
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依托单位:
SELECTIVE SIGMA LIGANDS: DESIGN SYNTHESIS & EVALUATION
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批准号:3384909
-
项目类别:
-
资助金额:$16.0万
-
财政年份:1991
-
负责人:RICHARD A GLENNON
-
依托单位:
DRUG DISCRIMINATION SYMPOSIUM CONFERENCE GRANT
-
批准号:3434380
-
项目类别:
-
资助金额:$1.5万
-
财政年份:1990
-
负责人:RICHARD A GLENNON
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依托单位:
CHEMICAL/BEHAVIORAL STUDIES ON HALLUCINOGENIC AGENTS
-
批准号:6175031
-
项目类别:
-
资助金额:$26.94万
-
财政年份:1989
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负责人:RICHARD A GLENNON
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依托单位:
CHEMICAL/BEHAVIORIAL STUDIES ON HALLUCINOGENIC AGENTS
-
批准号:2116456
-
项目类别:
-
资助金额:$24.06万
-
财政年份:1989
-
负责人:RICHARD A GLENNON
-
依托单位:
CHEMICAL/BEHAVIORAL STUDIES ON HALLUCINOGENIC AGENTS
-
批准号:7050224
-
项目类别:
-
资助金额:$29.3万
-
财政年份:1989
-
负责人:RICHARD A GLENNON
-
依托单位:
CHEMICAL/BEHAVIORIAL STUDIES ON HALLUCINOGENIC AGENTS
-
批准号:2390973
-
项目类别:
-
资助金额:$23.71万
-
财政年份:1989
-
负责人:RICHARD A GLENNON
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依托单位:
海外基金