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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Design, synthesis and melatoninergic activity of new unsubstituted and beta,beta'-difunctionalised 2,3-dihydro-1H-pyrrolo(3,2,1-ij)quinolin-6-alkanamides.
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Design, synthesis and melatoninergic activity of new unsubstituted and beta,beta'-difunctionalised 2,3-dihydro-1H-pyrrolo(3,2,1-ij)quinolin-6-alkanamides.

机译：新的未取代的和β，β'-双官能化的2,3-二氢-1H-吡咯并（3,2,1-ij）喹啉-6-烷酰胺的设计，合成和黑素能活性。

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摘要

A series of new 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-6-alkanamides, with and without alkyl and cycloalkyl moieties in the beta-position of the alkanamido side chain, have been prepared and tested for their ability to activate pigment granule aggregation in Xenopus laevis melanophores and bind to the recombinant human MT(1) and MT(2) melatonin receptor subtypes expressed in NIH 3T3 cells. An increase of the spacer's length in the side chain by a methylene unit (from 17d to 21d) leads to a six-fold decrease in antagonistic activity. On the other hand, the introduction of two methyl groups in the beta-position of the side chain of 17a induces agonist potency (compound 24), implying thus that the two beta-methyl groups are not only tolerated by the receptor, but constitute functional probes in its dynamic agonist-antagonist conformational equilibrium. The presence of more bulky beta-substituents, regardless of the size of the R group, compounds 24a,b, seems to lead to antagonism and to a noteworthy MT(2) subtype selectivity. Last, the new N1-C7 annulated derivatives presented herein are substantially more potent than their respective N1-C2 annulated counterparts, previously reported.
机译：制备了一系列新的2,3-二氢-1H-吡咯并[3,2,1-ij]喹啉-6-链烷酰胺，在链烷酰胺基侧链的β位带有或不带有烷基和环烷基部分，并且测试了它们激活非洲爪蟾黑色素细胞色素颗粒聚集并结合在NIH 3T3细胞中表达的重组人MT（1）和MT（2）褪黑素受体亚型的能力。亚甲基单元增加侧链间隔基的长度（从17d到21d），导致拮抗活性降低六倍。另一方面，在17a侧链的β位置引入两个甲基可诱导激动剂效价（化合物24），因此暗示这两个β甲基不仅可以被受体所耐受，而且还具有功能性在其动态激动剂-拮抗剂构象平衡中进行了探索。无论R基团的大小如何，化合物24a，b的存在都具有更大体积的β取代基，似乎导致拮抗作用，并引起了值得注意的MT（2）亚型选择性。最后，本文介绍的新的N1-C7环状衍生物比以前报道的各自的N1-C2环状衍生物更有效。

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