Abstract：
Herein the evolution in the development of new sigma (sigma) receptor ligands since the middle \'90s by our research group is reported. In the effort to contribute to the identification of the structural features for high-affinity ligands selective versus serotonin, dopamine and other CNS-related receptors, two general classes of (naphthalene)alkylamine compounds were prepared and explored, with the aim of addressing the affinities toward the two recognized sigma receptor subtypes. The common template of these compounds was mainly an unsubstituted or methoxy-substituted naphthalene or tetralin nucleus, linked by an alkyl spacer to a substituted piperazine or piperidine ring. The design of new ligands was thought keeping in mind their possible application as PET diagnostic tools and fluorescence tools. High-affinity sigma(2) receptor ligands were found among N-cyclohexylpiperazine derivatives, such as 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (3) (PB 28), when they were assayed in radioligand binding with [(3)H]-DTG in rat liver. Unfortunately, these ligands were all devoid of a significant selectivity relative to sigma(1) receptor whose binding was assayed with (+)-[(3)H]-pentazocine in guinea pig brain. Nevertheless, compound 3 had previously shown to be 40-fold selective with a slightly different binding method in animals\' tissues. Moreover, it demonstrated 46-fold and 59-fold sigma(2) versus sigma(1) receptor binding selectivity in MCF7 and MCF7 ADR tumor cell lines respectively. In the class of piperazines, also high-affinity sigma(1) receptor ligands were found, possibly due to the presence of a double N-atom and an additional reverse mode of binding. Piperidine derivatives were investigated as high-affinity and selective sigma(1) receptor ligands leading to some 3,3-dimethylpiperidines such as 3,3-dimethyl-1-[3-(6-methoxynaphthalen-1-yl)propyl]piperidine (69) which resulted to be highly selective relative to the sigma(2) receptor. For the best ligands, functional assays were conducted in order to investigate agonist/antagonist activity. The effect of chirality in the intermediate methyl-alkyl chain was explored for a class of 4-methylpiperidines linked to some (4-chlorophenoxy)alkyl moieties, and compound (-)-(S)-92 emerged as the most selective sigma(1) relative to sigma(2) receptor ligand.
摘要：
本文报道了我们研究小组自90年代中期以来新sigma（sigma）受体配体的发展。为了有助于鉴定高亲和力配体相对于血清素的选择性结构特征，多巴胺和其他中枢神经系统相关受体，制备和探索了两类(萘)烷基胺化合物，目的是解决对两种公认的σ受体亚型的亲和力。这些化合物的共同模板主要是未取代或甲氧基取代的萘或四氢萘核，通过烷基间隔基连接至取代的哌嗪或哌啶环。新配体的设计被认为是考虑到它们作为PET诊断工具和荧光工具的可能应用。在N-环己基哌嗪衍生物中发现了高亲和力σ（2）受体配体，例如1-环己基-4-[3-（5-甲氧基-1,2,3,4-四氢萘-1-基）丙基]哌嗪（3）（PB28），当它们在大鼠肝脏中与[（3）H]-DTG的放射性配体结合时进行测定。不幸的是,这些配体相对于sigma（1）受体都没有明显的选择性，sigma（1）受体的结合在豚鼠脑中用（）-[（3）H]-喷他佐辛测定。然而，先前已显示化合物3在动物组织中具有40倍的选择性，结合方法略有不同。此外，它在MCF7和MCF7ADR肿瘤细胞系中分别显示46倍和59倍σ(2)与σ(1)受体结合选择性。在哌嗪类，还发现了高亲和力σ（1）受体配体，可能是由于存在双N原子和另外的反向结合模式。研究了哌啶衍生物作为高亲和力和选择性σ(1)受体配体,其导致一些3,3-二甲基哌啶,例如3,3-二甲基-1-[3-(6-甲氧基萘-1-基)丙基]哌啶(69),其导致相对于σ(2)受体具有高度选择性。对于最好的配体，进行功能测定以研究激动剂/拮抗剂活性。对于与某些（4-氯苯氧基）烷基部分连接的一类4-甲基哌啶，探索了中间体甲基-烷基链中手性的影响，和化合物(-)-(S)-92作为相对于σ(2)受体配体的最具选择性的σ(1)出现。
