Bertha C M, Vilner B J, Mattson M V, Bowen W D, Becketts K, Xu H, Rothman R B, Flippen-Anderson J L, Rice K C
Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Med Chem. 1995 Nov 24;38(24):4776-85. doi: 10.1021/jm00024a005.
The determination of the structure and function of the sigma receptor subtypes and their physiological role(s) has been impeded by the unavailability of selective ligands. We have developed a new class of sigma subtype selective receptor ligands that are (E)-8-benzylidene derivatives of the synthetic opioid (+/-)-, (+)-, and (-)-2-methyl-5-(3-hydroxyphenyl)morphan-7-one (1). The derivatives can be prepared by reaction of 1, (+)-1, and (-)-1 with the appropriate benzaldehyde under Claisen-Schmidt conditions. Incorporation of substituted (E)-8-benzylidene moieties onto the 7-keto precursor of (+)-2-methyl-5-(3-hydroxyphenyl)morphan, (+)-1, produces compounds (-)-2 through (-)-7 (5.8-32.0 nM, sigma 1), which have between a 25- and 131-fold increase in affinity for the sigma 1 receptor subtype relative to the keto precursor (+)-1 (Ki = 762 nM, sigma 1). Compound (-)-2 is the most selective of this group (16-fold) for the sigma 1 subtype versus sigma 2. Substitution of an (E)-8-benzylidene moiety onto the 7-keto precursor of (-)-2-methyl-5-(3-hydroxyphenyl)morphan, (-)-1, produces compounds (+)-2-(+)-9 (6.4-52.6 nM, sigma 2), which have at least a 475-3906-fold increase in affinity for the sigma 2 receptor subtype relative to the keto precursor (-)-1 (Ki = 25 x 10(3) nM). This enhancement of sigma 2 receptor affinity is accompanied by substantial selectivity of all of these dextrorotatory products for the sigma 2 relative to the sigma 1 subtype (32-238-fold), and thus, they are among the most sigma 2 selective compounds currently known. Furthermore, the sigma 1 subtype is highly enantioselective for the levorotatory isomers, (-)-2-(-)-7 (41-1034-fold), whereas the sigma 2 subtype is only somewhat enantioselective for the dextrorotatory isomers, (+)-2-(+)-7 (2.6-9.3-fold). All of these derivatives retain substantial affinity for the mu opioid receptor. Despite the high affinity of the dextrorotatory derivatives for the mu opioid receptor, the high affinity and selectivity for sigma 2 over sigma 1 sites will surely prove beneficial as tools for the delineation of the function and physiological role of sigma 2 receptors.
由于缺乏选择性配体，σ受体亚型的结构与功能及其生理作用的确定受到了阻碍。我们开发了一类新型的σ亚型选择性受体配体，它们是合成阿片类药物（±）-、（+）-和（-）-2-甲基-5-（3-羟基苯基）吗啡喃-7-酮（1）的（E）-8-亚苄基衍生物。这些衍生物可通过1、（+）-1和（-）-1与适当的苯甲醛在克莱森-施密特条件下反应制备。将取代的（E）-8-亚苄基部分引入（+）-2-甲基-5-（3-羟基苯基）吗啡喃（+）-1的7-酮前体上，生成化合物（-）-2至（-）-7（5.8 - 32.0 nM，σ1），相对于酮前体（+）-1（Ki = 762 nM，σ1），它们对σ1受体亚型的亲和力增加了25至131倍。化合物（-）-2是该组中对σ1亚型与σ2亚型选择性最高的（16倍）。将（E）-8-亚苄基部分取代到（-）-2-甲基-5-（3-羟基苯基）吗啡喃（-）-1的7-酮前体上，生成化合物（+）-2至（+）-9（6.4 - 52.6 nM，σ2），相对于酮前体（-）-1（Ki = 25×10³ nM），它们对σ2受体亚型的亲和力至少增加了475至3906倍。σ2受体亲和力的这种增强伴随着所有这些右旋产物对σ2相对于σ1亚型的显著选择性（32至238倍），因此，它们是目前已知的对σ2选择性最高的化合物之一。此外，σ1亚型对左旋异构体（-）-2至（-）-7具有高度对映选择性（41至1034倍），而σ2亚型对右旋异构体（+）-2至（+）-7仅具有一定程度的对映选择性（2.6至9.3倍）。所有这些衍生物对μ阿片受体仍保留相当大的亲和力。尽管右旋衍生物对μ阿片受体具有高亲和力，但对σ2位点相对于σ1位点的高亲和力和选择性肯定将被证明是用于阐明σ2受体功能和生理作用的有用工具。
