New sigma and 5-HT1A receptor ligands: omega-(tetralin-1-yl)-n-alkylamine derivatives
New sigma and 5-HT1A receptor ligands: omega-(tetralin-1-yl)-n-alkylamine derivatives
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DOI：
10.1021/jm950409c
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发表时间：
1996-01-05
影响因子：
7.3
通讯作者：
Lucchi, L
中科院分区：
文献类型：
--
作者：
Berardi, F;Colabufo, NA;Lucchi, L
为了提高亲和力和选择性，合成了两个结构上与苯并吗啉相关的化合物，它们是通过对5-HT1a高亲和力和中等a亲和力的芳基哌嗪进行结构修饰而得到的。所有新化合物都是N-substituted-omega-(1，2，3，4-tetrahydronaphthalen-1-yl)-或-omega-(1，2-dihydronaphthalen-4-yl)-n-alkylamines，在某些情况下，四氢呋喃部分上有甲氧基。在Sigma([H-3]DTG和[H-3]-(+)-Pazazocine)、D-2多巴胺能、5-HT1a和5-HT2能以及PCP(苯环利定)受体上进行放射配基结合分析。第一组以4-(1-取代)哌嗪部分为烷基末端片段的化合物表现出中等到高的Sigma亲和力(K-I=5.3-139nM)，其中最具活性和选择性的是1-cyclohexyl-4-[3-(5-methoxy-1，2，3，4-tetrahydronaphthalen-1-yl)-n-proyl]piperazine(14)，可能具有明显的α(2)亲和力(在[H-3]dtg上的K-i=5.3nM，在[H-3]-(+)-五唑碱上的Ki=71 nM)。此外，化合物13是一种1-苄基哌嗪类似物，在[H-3]-5-HT和[H-3]-DTG上保持了较高的5-HT1A和Sigma亲和力([H-3]-5-HT的K-I=3.6 nm和[H-3]DTG的K-I=7.0 nm)。第二组化合物包括一些可以考虑的3-(5-methoxy-1，2，3，4-tetrahydronaphthalen-1-yl)-n-propylamine的N-苯基烷基衍生物。为4-取代-1-芳基哌嗪的开链衍生物。在对Sigma结合活性较低的化合物中，对N-(3-苯丙基)衍生物21(K-I=4.4 nm)有较高的5-HT1a亲和力，表现出很好的选择性。
Two series of compounds that are structurally related to benzomorphans, derived by structural modification of arylpiperazines with high 5-HT1A affinity and moderate a affinity, were prepared in order to increase a affinity and selectivity. All new compounds are N-substituted-omega-(1,2,3,4-tetrahydronaphthalen-1-yl)- or -omega-(1,2-dihydronaphthalen-4-yl)-n-alkylamines with, in some cases, a methoxy group on the tetralin moiety. They were tested in radioligand binding assays on sigma ([H-3]DTG and [H-3]-(+)-pentazocine), D-2 dopaminergic, 5-HT1A and 5-HT2 serotonergic, and PCP (phencyclidine) receptors. A first set of compounds bearing a 4-(1-substituted)piperazine moiety as terminal fragment on the alkyl chain showed moderate to high sigma affinity (K-i = 5.3-139 nM), the most active and selective being 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-proyl]piperazine (14), with probable pronounced alpha(2) affinity (K-i = 5.3 nM on [H-3]DTG and K-i = 71 nM on [H-3]-(+)-pentazocine). Moreover, compound 13, a 1-benzylpiperazine analogue of 14, preserved a dual high 5-HT1A and sigma affinity (K-i = 3.6 nM on [H-3]-5-HT and K-i = 7.0 nM on [H-3]DTG). The second set of compounds includes some N-phenylalkyl derivatives of 3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propylamine that can be considered. to be open-chain derivatives of 4-substituted-1-arylpiperazines. Among these compounds that had a lower activity toward sigma binding sites, a high 5-HT1A affinity was found for the N-(3-phenylpropyl) derivative 21 (K-i = 4.4 nM) which demonstrated very good selectivity.