Klein M, Musacchio J M
Department of Pharmacology, N.Y.U. Medical Center, NY 10016.
Life Sci. 1990;47(18):1625-34. doi: 10.1016/0024-3205(90)90367-z.
Computer-assisted analysis of self- and cross-displacement studies between dextromethorphan (DM) and (+)-3-(3-hydroxyphenyl)-N-(1-propyl) piperidine ((+)-3-PPP) demonstrated in the rat brain the existence of two high-affinity and one low-affinity binding site for each ligand. One high-affinity site is the common DM1/sigma 1 site, the affinity of which is allosterically increased 4 to 5-fold by 10 microM ropizine. The Kd values of the DM1/sigma 1 for DM and (+)-3-PPP are 17 and 11 nM respectively. DM binds to the second high-affinity site (R2) with a Kd of 15 nM; this site has low affinity for (+)-3-PPP. Conversely, (+)-3-PPP binds with high affinity (Kd 53 nM) to another site (R3), that has low-affinity for DM. The Bmax of the common DM1/sigma 1 site in the rat is about ten times smaller than that in the guinea pig. Thus, extreme caution should be exercised in extrapolating from one species to another. Since DM and most sigma ligands bind to more than one site, not all of which are shared, it is important not to attribute the complex pharmacological effects of these ligands to a single hypothetical receptor.
对右美沙芬（DM）和（+）-3-（3-羟苯基）-N-（1-丙基）哌啶（（+）-3-PPP）之间的自身置换和交叉置换研究进行计算机辅助分析，结果表明，在大鼠脑中，每种配体都存在两个高亲和力结合位点和一个低亲和力结合位点。一个高亲和力位点是常见的DM1/σ1位点，10μM罗哌嗪可使其亲和力变构增加4至5倍。DM1/σ1对DM和（+）-3-PPP的Kd值分别为17 nM和11 nM。DM以15 nM的Kd值与第二个高亲和力位点（R2）结合；该位点对（+）-3-PPP的亲和力较低。相反，（+）-3-PPP以高亲和力（Kd 53 nM）与另一个对DM亲和力较低的位点（R3）结合。大鼠中常见的DM1/σ1位点的Bmax约比豚鼠中的小十倍。因此，在从一个物种推断到另一个物种时应格外谨慎。由于DM和大多数σ配体结合到多个位点，且并非所有位点都是共享的，因此重要的是不要将这些配体的复杂药理作用归因于单一的假设受体。
