Vangveravong S, Kanthasamy A, Lucaites V L, Nelson D L, Nichols D E
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
J Med Chem. 1998 Dec 3;41(25):4995-5001. doi: 10.1021/jm980318q.
A series of four racemic ring-substituted trans-2-(indol-3-yl)cyclopropylamine derivatives was synthesized and tested for affinity at the 5-HT1A receptor, by competition with [3H]-8-OH-DPAT in rat hippocampal homogenates, and for affinity at the agonist-labeled cloned human 5-HT2A, 5-HT2B, and 5-HT2C receptor subtypes. None of the compounds had high affinity for the 5-HT1A receptor, with the 5-methoxy substitution being most potent (40 nM). At the 5-HT2A and 5-HT2B receptor isoforms, most of the compounds lacked high affinity. At the 5-HT2C receptor, however, affinities were considerably higher. The 5-fluoro-substituted compound was most potent, with a Ki at the 5-HT2C receptor of 1.9 nM. In addition, the 1R,2S-(-) and 1S,2R-(+) enantiomers of the unsubstituted compound were also evaluated at the 5-HT2 isoforms. While the 1R,2S enantiomer had higher affinity at the 5-HT2A and 5-HT2B sites, the 1S,2R isomer had highest affinity at the 5-HT2C receptor. This reversal of stereoselectivity may offer leads to the development of a selective 5-HT2C receptor agonist. The cyclopropylamine moiety therefore appears to be a good strategy for rigidification of the ethylamine side chain only for tryptamines that bind to the 5-HT2C receptor isoform.
合成了一系列四种外消旋环取代的反式-2-(吲哚-3-基)环丙胺衍生物，并通过在大鼠海马匀浆中与[3H]-8-OH-DPAT竞争来测试其对5-HT1A受体的亲和力，以及对激动剂标记的克隆人5-HT2A、5-HT2B和5-HT2C受体亚型的亲和力。这些化合物均对5-HT1A受体没有高亲和力，其中5-甲氧基取代的化合物活性最强（40 nM）。在5-HT2A和5-HT2B受体亚型中，大多数化合物缺乏高亲和力。然而，在5-HT2C受体上，亲和力要高得多。5-氟取代的化合物活性最强，其在5-HT2C受体上的Ki为1.9 nM。此外，还对未取代化合物的1R,2S-(-)和1S,2R-(+)对映体在5-HT2亚型上进行了评估。虽然1R,2S对映体在5-HT2A和5-HT2B位点具有较高的亲和力，但1S,2R异构体在5-HT2C受体上具有最高的亲和力。这种立体选择性的反转可能为开发选择性5-HT2C受体激动剂提供线索。因此，对于与5-HT2C受体亚型结合的色胺类化合物，环丙胺部分似乎是使乙胺侧链刚性化的良好策略。
