de Costa B R, Dominguez C, He X S, Williams W, Radesca L, Bowen W
Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
J Med Chem. 1992 Nov 13;35(23):4334-43. doi: 10.1021/jm00101a011.
The synthesis and sigma receptor affinity of a series of conformationally restricted derivatives of 2-(1-pyrrolidinyl)-N-[2-(3,4-dichlorophenyl)ethyl]-N-methylethylenedi amine (1) is described. The pyrrolidinyl (or N,N-dialkyl),ethylenediamine,N-alkyl, and phenylethyl portions of this sigma receptor pharmacophore were restricted by its incorporation into 1,2-cyclohexanediamine-, pyrrolidine-, piperidine-, homopiperidine-, and tetrahydroisoquinoline-containing ligands. The sigma receptor binding affinities of these compounds were determined using 3H-pentazocine in guinea pig brain homogenates. The synthesis of all but one class was achieved by acylation and alane reduction of the appropriate diamine precursors whose synthesis is also reported. sigma receptor affinities ranged from 1.34 nM for 6,7-dichloro-2-[2-(1-pyrrolidinyl)ethyl]tetrahydroisoquinoline (12) to 455 nM for (1R,2R)-trans-N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2- (1-pyrrolidinyl)cyclohexylamine [(-)-4]. In this displacement assay, (+)-pentazocine exhibited a Ki of 3.1 nM while DTG and haloperidol showed Ki values of 27.7 and 3.7 nM, respectively. The conformationally free parent compound 1 exhibited a Ki value of 2.1 nM. Comparison of both the sigma receptor affinities and nitrogen atom geometry of the compounds revealed that a gauche relation of the nitrogen atoms of cis-1,2-cyclohexanediamines is not imperative for high affinity as we had previously thought. It is highly likely that nitrogen lone pair orientations and steric factors on the aliphatic portions of these ligands play a major role in the sigma receptor binding of this pharmacophore.
描述了一系列2-(1-吡咯烷基)-N-[2-(3,4-二氯苯基)乙基]-N-甲基乙二胺(1)的构象受限衍生物的合成及其与σ受体的亲和力。该σ受体药效基团的吡咯烷基(或N,N-二烷基)、乙二胺、N-烷基和苯乙基部分通过将其并入含1,2-环己二胺、吡咯烷、哌啶、高哌啶和四氢异喹啉的配体中而受到限制。使用3H-喷他佐辛在豚鼠脑匀浆中测定了这些化合物与σ受体的结合亲和力。除一类化合物外，所有化合物的合成均通过适当二胺前体的酰化和铝氢化还原实现，二胺前体的合成也有报道。σ受体亲和力范围从6,7-二氯-2-[2-(1-吡咯烷基)乙基]四氢异喹啉(12)的1.34 nM到(1R,2R)-反式-N-[2-(3,4-二氯苯基)乙基]-N-甲基-2-(1-吡咯烷基)环己胺[(-)-4]的455 nM。在该置换试验中，(+)-喷他佐辛的Ki值为3.1 nM，而DTG和氟哌啶醇的Ki值分别为27.7和3.7 nM。构象自由的母体化合物1的Ki值为2.1 nM。对化合物的σ受体亲和力和氮原子几何结构的比较表明，顺式-1,2-环己二胺的氮原子的gauche关系对于高亲和力并非如我们先前认为的那样必不可少。这些配体脂肪族部分上的氮孤对取向和空间因素很可能在该药效基团与σ受体的结合中起主要作用。
