Effect of ring fluorination on the pharmacology of hallucinogenic tryptamines
Effect of ring fluorination on the pharmacology of hallucinogenic tryptamines
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DOI：
10.1021/jm000339w
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发表时间：
2000-11-30
影响因子：
7.3
通讯作者：
Nichols, DE
中科院分区：
文献类型：
--
作者：
Blair, JB;Kurrasch-Orbaugh, D;Nichols, DE
合成了一系列致幻性色胺 N,N-二乙基色胺 (DET)、4-羟基-N,N-二甲基色胺（4-OH-DMT、赛洛辛）和 5-甲氧基-DMT 的氟化类似物，以研究 6-氟-DET 作为致幻剂失活的可能解释，并确定氟化对致幻剂的影响。 这些化合物在血清素受体亚型上的分子识别和激活。使用体内行为测定法评估目标化合物的致幻剂样和 6-HT1A 激动剂活性，并使用体外放射性配体竞争测定法评估其在 5-HT2A、5-HT2C 和 5-HT1A 受体位点的亲和力。测定了所有化合物的 5-HT2A 受体功能活性。此外，某些化合物的功能活性是在 5-HT1A 受体上测定的。使用 LSD 训练的大鼠在两杆药物辨别范式中评估，所有氟化类似物的致幻剂样活性均减弱或消除。其中一种色胺 4-氟-5-甲氧基-DMT (6) 显示出高 5-HT1A 激动剂活性，其效力大于 5-HT1A 激动剂 8-OH-DPAT。使用经过训练辨别5-HT1A激动剂LY293284的大鼠的两杆药物辨别范例中的6的ED50为0.17μmol/kg，并且[H-3]8-OH-DPAT标记的5-HT1A受体的K-i为0.23nM。结果表明，致幻色胺的氟化通常对5-HT2A/2C受体亲和力或内在活性影响很小。然而，在除一个例子之外的所有例子中，对 5-HT1A 受体的亲和力都降低了，并且所有测试的化合物都是完全激动剂，但对该血清素受体亚型的功能效力降低。一个值得注意的例外是 4-氟-5-甲氧基-DMT (6)，它显着增强了 5-HT1A 受体亲和力和功能效力。虽然人们普遍认为致幻活性是由 5-HT2A 受体激活引起的，但目前的结果表明 5-HT1A 受体与色胺的参与可能发挥作用。
A series of fluorinated analogues of the hallucinogenic tryptamines N,N-diethyltryptamine (DET), 4-hydroxy-N,N-dimethyltryptamine (4-OH-DMT, psilocin), and 5-methoxy-DMT was synthesized to investigate possible explanations for the inactivity of 6-fluoro-DET as a hallucinogen and to determine the effects of fluorination on the molecular recognition and activation of these compounds at serotonin receptor subtypes. The target compounds were evaluated using in vivo behavioral assays for hallucinogen-like and 6-HT1A agonist activity and in vitro radioligand competition assays for their affinity at 5-HT2A, 5-HT2C, and 5-HT1A receptor sites. Functional activity at the 5-HT2A receptor was determined for all compounds. In addition, for some compounds functional activity was determined at the 5-HT1A receptor. Hallucinogen-like activity, evaluated in the two-lever drug discrimination paradigm using LSD-trained rats, was attenuated or abolished for all of the fluorinated analogues. One of the tryptamines, 4-fluoro-5-methoxy-DMT (6), displayed high 5-HT1A agonist activity, with potency greater than that of the 5-HT1A agonist 8-OH-DPAT. The ED50 Of 6 in the two-lever drug discrimination paradigm using rats trained to discriminate the 5-HT1A agonist LY293284 was 0.17 mu mol/kg, and the K-i at [H-3] 8-OH-DPAT-labeled 5-HT1A receptors was 0.23 nM. The results indicate that fluorination of hallucinogenic tryptamines generally has little effect on 5-HT2A/2C receptor affinity or intrinsic activity. Affinity at the 5-HT1A receptor was reduced, however, in all but one example, and all of the compounds tested were full agonists but with reduced functional potency at this serotonin receptor subtype. The one notable exception was 4-fluoro-5-methoxy-DMT (6), which had markedly enhanced 5-HT1A receptor affinity and functional potency. Although it is generally considered that hallucinogenic activity results from 5-HT2A receptor activation, the present results suggest a possible role for involvement of the 5-HT1A receptor with tryptamines.