ANANDAMIDE CONFORMERS TO PROBE THE CANNABINOID RECEPTOR
大麻素构象探索大麻素受体
基本信息
- 批准号:2749124
- 负责人:
- 金额:$ 12.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1996
- 资助国家:美国
- 起止时间:1996-09-01 至 2001-07-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION: (Applicant's Abstract)
The systematic study of analogs of the endogenous cannabimimetic,
anandamide, has the long term, health related potential to further knowledge
of the biochemical mechanism of action of this neurotransmitter and the new
neurochemical system it represents. Mapping of ligand interaction sites and
the identification of receptor subtypes are additional objectives. Also,
analogs could be generated with dissociated pharmacological effects
resulting in more specific drugs and biochemical probes with psycho dynamic
activities of interest. These have potential application to studies of drug
abuse, brain function, and immuno-modulation. The specific aims of the
proposed work is the design, synthesis, pharmacological testing, and
molecular modeling of conformationally restricted anandamide analogs to
probe a sector of conformational space that chemical and computational data
suggest as the active conformation of anandamide. It is theorized that the
active conformation of anandamides is a bent or "J" like structure which
exhibits remarkable overlap with active cannabinoids as regards both shape
and electrostatic potentials at its receptor accessible surface. Locking
such conformations is expected to enhance activities and potentially
dissociate biological effects in this class of compounds. Compounds
designed to test the theory are ring constrained structures, based on
preliminary molecular dynamics studies of anandamide and reported chemistry
of other arachidonic acid derivatives, that examines the hypothesized sector
of conformational space with small, medium and macrocyclic ring analogs.
The compounds explore the effects of the position of the bend in the acyclic
20-carbon chain of anandamide, the configurational differences at chiral
centers, and the degree of conformational freedom as influenced by various
ring systems. It is further theorized that interaction between the pi
electrons of the ligand and cationic sites in the receptor play a key role
in binding. This is tested in analogs with both enhanced and reduced pi
character in a way that separates the conformational and the electrostatic
effects of the carbon-carbon double bonds. Putative metabolites of
anandamide and the analogs are examined as they are potential active forms
of this class of ligands. The research program is designed to test and
evolve an SAR theory and discover active analogs by computationally guided
synthesis, in vitro and in vivo testing, and computational analysis to
refine subsequent cycles of design, synthesis and testing. Testing will
involve accepted receptor binding assays, inhibition of mouse isolated vas
deferens twitch response, and in vivo testing in the mouse to identify
active compounds.
描述:(申请人摘要)
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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HERBERT H SELTZMAN其他文献
HERBERT H SELTZMAN的其他文献
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{{ truncateString('HERBERT H SELTZMAN', 18)}}的其他基金
ANANDAMIDE CONFORMERS TO PROBE THE CANNABINOID RECEPTOR
大麻素构象探索大麻素受体
- 批准号:
2458453 - 财政年份:1996
- 资助金额:
$ 12.25万 - 项目类别:
ANANDAMIDE CONFORMERS TO PROBE THE CANNABINOID RECEPTOR
大麻素构象探索大麻素受体
- 批准号:
2123524 - 财政年份:1996
- 资助金额:
$ 12.25万 - 项目类别:
ANANDAMIDE CONFORMERS TO PROBE THE CANNABINOID RECEPTOR
大麻素构象探索大麻素受体
- 批准号:
2616076 - 财政年份:1996
- 资助金额:
$ 12.25万 - 项目类别:
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