STEREOCHEMICAL ASPECTS OF HALLUCINOGENESIS

致幻剂的立体化学方面

• 批准号: 3207156
• 负责人: DAVID E NICHOLS
• 金额: $ 15.67万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-07-15 至 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3207156
• 关键词: X ray crystallography; autoradiography; behavioral medicine; brain metabolism; chemical substitution; chemical synthesis; conformation; dopamine receptor; drug metabolism; ergolines; indoles; isomer; laboratory rat; lysergic acid diethylamide; mass spectrometry; nuclear magnetic resonance spectroscopy; receptor binding; serotonin receptor; stereochemistry; X ray crystallography; autoradiography; behavioral medicine; brain metabolism; chemical substitution; chemical synthesis; conformation; dopamine receptor; drug metabolism; ergolines; indoles; isomer; laboratory rat; lysergic acid diethylamide; mass spectrometry; nuclear magnetic resonance spectroscopy; receptor binding; serotonin receptor; stereochemistry

This proposal presents for synthesis and pharmacological evaluation: (1) a series of lysergic acid amides wherein the amide substituent is derived from a chiral amine, (2) a tricyclic ergoline analogue where the pyrrole ring of the ergoline has been replaced with a dihydrofuran ring and, (3) a benz[cd]indole with a pyrrolidine ring cis-fused across the 4-amino-C(3) positions. The latter two series will be resolved into their enantiomers. All compounds will be tested for substitution in the two-lever drug discrimination paradigm, in rats trained to discriminate saline from ip injections of LSD tartrate (0.08 mg/kg). Compounds will also be examined for affinity at the serotonin 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, and 5-HT2, alphal- and alpha2-adrenergic, and dopamine D1 and D2 receptors. Collaborative arrangements have been made to obtain functional measures of those compounds that have high affinity for the serotonin and dopamine receptor subtypes (effects on PI turnover and cAMP). For the lysergamides, conformational energy calculations will be performed, and pKa and log P values will also be determined. Hallucinogenic lysergamides have not been adequately studied in the past and it is anticipated that some quantitative combination of variables for the lysergamides, and a consideration of the conformational energies, may allow correlation with the in vivo behavioral potency, thus identifying the relative importance and the nature of the interaction of LSD-like ligands with the various monoamine receptors. A particular power of this approach is the use of diastereomeric lysergamides with chiral amide substituents. The two synthetic partial ergoline analogues will be used to test the hypotheses that: (1) a 2,3-dihydrobenzofuran can serve as an effective bioisostere for an indole and, (2) that ergolines may undergo a D-ring inversion on' binding to some monoamine receptors to present the unshared electron pair of the amino group on the upper, or beta-face of the ergoline molecule. These studies will lead to a greater understanding of the nature of the ligand-receptor interaction for the monoamine receptors studied, as well as to a better understanding of the relative importance of these particular monoamine receptors in the action of LSD and other hallucinogens.

该提案提出了用于合成和药理评估的建议：（1） 一系列酰胺取代基的一系列脂肪酸酰胺 从手性胺中，（2）三环类黄类似物 ergoline的环已被二氢呋喃环代替，（3） 苯并[CD]吲哚，吡咯烷环顺式融合在整个 4-氨基-C（3）位。 后两个系列将解决 他们的对映异构体。 所有化合物都将在 两级药物歧视范式，在接受歧视的大鼠中 IP注射LSD Tartrate（0.08 mg/kg）的盐水。 化合物会 还可以在5- ht1a，5-ht1b，5-ht1c的5- ht1a，5-ht1c上检查亲和力 5-HT1D和5-HT2，α2-肾上腺素能以及多巴胺D1和D2 受体。 已经制定了协作安排 那些对较高亲和力的化合物的功能度量 5-羟色胺和多巴胺受体亚型（对PI周转和影响的影响 营）。 对于溶血胺，构象能计算将是 执行，并且还将确定PKA和log P值。 过去尚未对幻影症的溶血酰胺进行充分研究 预计变量的某些定量组合 钙胺和对构象能的考虑可能 允许与体内行为效力相关，从而识别 LSD样相互作用的相对重要性和性质 配体具有各种单胺受体。 这个特定的力量 方法是使用心性酰胺的非映异构体溶血体 取代基。 将使用两个合成部分类似物 测试以下假设：（1）2,3-二氢苯并呋喃可以用作 吲哚和（2）Ergolines可能经历A 与某些单胺受体结合的d-ring反转以呈现 上部或β面的未共享电子对 ergoline分子。 这些研究将导致更大的 理解配体 - 受体相互作用的性质 单胺受体研究，以及更好地理解 这些特定的单胺受体在作用中的相对重要性 LSD和其他致幻剂。