de Costa B R, He X S, Linders J T, Dominguez C, Gu Z Q, Williams W, Bowen W D
Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
J Med Chem. 1993 Aug 6;36(16):2311-20. doi: 10.1021/jm00068a007.
As a continuation of our earlier study (J. Med. Chem. 1992, 35, 4334-4343) we conformationally restricted the sigma-receptor ligand 2-(1-pyrrolidinyl)-N-[2-(3,4-dichlorophenyl)ethyl]-N-methylethylamine (1) by incorporating it into a series of homologous piperazines 3-9 and homopiperazines 10 and 11, diazabicyclononanes and decanes, bridgehead bicyclooctanes and nonanes as well as other miscellaneous compounds. sigma-Receptor binding affinities were obtained using 3H-pentazocine in guinea pig brain membrane sigma 1 sites. The studies suggest that the nitrogen lone pair orientation found in the piperazines affords the strongest binding interaction. Other nitrogen lone pair orientations or compounds representing unlikely staggered conformations of 1 [ as in 4-[2-(3,4-dichlorophenyl)ethyl]-1,4-diazabicyclo[3.2.2]nonane (16)] show very weak sigma interaction. Comparison of the binding data of different N-substituted homologues of 1 with those of the 1-[2-(3,4-dichlorophenyl)ethyl]-4-alkylpiperazines suggests that the two nitrogen atoms of 1 are working in opposition to one another in terms of their sensitivity to steric bulk. The high binding affinity of the 1,4-diazabicyclo[4.3.0]nonanes 12 suggests that these may approximate the methyl and pyrrolidine ring conformations found in 1 when it is bound to the sigma receptor. Compound 12 exhibited a 4-fold enantioselectivity favoring (+)-12. The synthesis of 6,7-dichloro-2-[[2-(1-pyrrolidinyl)ethyl]amino]tetralin (19) and its desmethyl derivative 20 permitted constraint of the 3,4-dichlorophenyl and N-methyl moieties of 1 into a gauche orientation. The binding data suggests that this conformation in 1 favors strong binding interaction at sigma-receptors. sigma-Receptor Ki's ranged from 0.55 nM for 1-[2-(3,4-dichlorophenyl)ethyl]-4-n-butylpiperazine (7) to 654 nM for 16. Overall comparison of the results indicate that 1 is subject to considerable conformational freedom and suggests that the sigma receptor is not subject to rigid stereochemical restraints with 1. These results add to our earlier study where we restrained 1 using simple monocyclic heterocycles.
作为我们早期研究（《药物化学杂志》1992年，第35卷，4334 - 4343页）的延续，我们通过将σ受体配体2-(1-吡咯烷基)-N-[2-(3,4-二氯苯基)乙基]-N-甲基乙胺（1）并入一系列同系哌嗪3 - 9、高哌嗪10和11、二氮杂双环壬烷和癸烷、桥头双环辛烷和壬烷以及其他杂环化合物中，对其构象进行了限制。使用³H-喷他佐辛在豚鼠脑膜σ1位点获得σ受体结合亲和力。研究表明，哌嗪中氮孤对的取向提供了最强的结合相互作用。其他氮孤对取向或代表1不太可能的交错构象的化合物[如4-[2-(3,4-二氯苯基)乙基]-1,4-二氮杂双环[3.2.2]壬烷（16）]显示出非常弱的σ相互作用。将1的不同N-取代同系物的结合数据与1-[2-(3,4-二氯苯基)乙基]-4-烷基哌嗪的结合数据进行比较表明，1的两个氮原子在对空间位阻的敏感性方面相互拮抗。1,4-二氮杂双环[4.3.0]壬烷12的高结合亲和力表明，当1与σ受体结合时，这些化合物可能接近1中发现的甲基和吡咯烷环构象。化合物12表现出4倍的对映选择性，有利于(+)-12。6,7-二氯-2-[[2-(1-吡咯烷基)乙基]氨基]四氢化萘（19）及其去甲基衍生物20的合成使得1的3,4-二氯苯基和N-甲基部分能够被限制为gauche取向。结合数据表明，1中的这种构象有利于在σ受体处产生强结合相互作用。σ受体的Ki值范围从1-[2-(3,4-二氯苯基)乙基]-4-正丁基哌嗪（7）的0.55 nM到16的654 nM。结果的总体比较表明，1具有相当大的构象自由度，并表明σ受体对1不存在严格的立体化学限制。这些结果补充了我们早期使用简单单环杂环限制1的研究。
