Abstract：
The introduction of arylmethyl substituents on the amine nitrogen atom of phenethylamines and tryptamines often results in profound increases in their affinity and functional activity at 5-HT2 serotonin receptors. To probe the sensitivity of this effect to substantially larger N-substituents, ten derivatives of the well-characterized psychedelic phenethylamine 2C-B were prepared by appending different dibenzo[b,d]furylmethyl (DBFM) moieties to the basic nitrogen. The DBFM group attached to the amino group through its 1-, -2-, or 3-position decreased affinity and agonist activity at the 5-HT2A/2C receptors. Substitution through the 4-position usually favored affinity for all three 5-HT2 receptor subtypes with compound 5 exhibiting 10- and 40-fold higher affinities at the 5-HT2A and 5-HT2C receptors, respectively, but less than fourfold selectivity among the three receptor subtypes. Nevertheless, all were relatively weak partial 5-HT2AR agonists, mostly in the low micromolar range, but full or nearly full agonists at the 5-HT2C subtype as determined in a calcium mobilization assay. Molecular docking simulations suggested that the dibenzofuryl portion dives more deeply into the orthosteric binding site of the 5-HT2A than the 5-HT2C receptor, interacting with the Trp3366.48 toggle switch associated with its activation, while the phenylamine moiety lies close to the extracellular side of the receptor. In conclusion, a very bulky N-substituent on a phenethylamine 5-HT2 receptor agonist is tolerated and may increase affinity if its orientation is appropriate. However, the Gq protein-mediated potencies are generally low, with low efficacy (relative to 5-HT) at the 5-HT2A receptor, somewhat higher efficacy at the 5-HT2B subtype, and full or nearly full efficacy at the 5-HT2C subtype.
摘要：
在苯乙胺和色胺的胺氮原子上引入芳基甲基取代基通常导致它们对5-HT2血清素受体的亲和力和功能活性的显着增加。为了探测这种效应对更大的N-取代基的敏感性，通过添加不同的二苯并[b，d]对碱性氮的呋喃甲基(DBFM)部分。DBFM基团通过其1-，-2-,或3位降低了对5-HT2A/2C受体的亲和力和激动剂活性。通过4位取代通常有利于所有三种5-HT2受体亚型的亲和力，化合物5对5-HT2A和5-HT2C受体的亲和力高10倍和40倍，分别,但三种受体亚型的选择性不到四倍。然而，都是相对较弱的部分5-HT2AR激动剂，大多在低微摩尔范围内，但在钙动员测定中确定的5-HT2C亚型完全或几乎完全激动剂。分子对接模拟表明，二苯并呋喃部分比5-HT2C受体更深入地潜入5-HT2A的正构结合位点，与激活相关的Trp3366.48拨动开关进行交互，而苯胺部分靠近受体的胞外侧。总之,苯乙胺5-HT2受体激动剂上非常大的N-取代基是耐受的，并且如果其方向合适，则可以增加亲和力。然而,Gq蛋白介导的效力通常较低，对5-HT2A受体具有低功效（相对于5-HT），5-HT2B亚型的疗效更高，5-HT2C亚型完全或几乎完全有效。
