Rothman R B, Xu H, Seggel M, Jacobson A E, Rice K C, Brine G A, Carroll F I
Unit on Receptor Studies, Laboratory of Medicinal Chemistry, NIDDK, Bethesda, MD 20892.
Life Sci. 1991;48(23):PL111-6. doi: 10.1016/0024-3205(91)90346-d.
The objective of this study was to determine the binding affinities of (+/-)-cis-N-[1-(2-hydroxy-2-phenylethyl)-3-methyl-4-piperidyl]- N-phenylpropanamide-HCI (RTI-4614-4), which is an analog of (+)-cis-3-methylfentanyl for opioid receptor subtypes. The Ki values (nM) of this agent for opioid receptor subtypes were as follows: mu (0.0055), delta (148), kappa 1 (84.8), kappa 2a (2275), and kappa 2b (22.3). The selectivity of this agent for the mu binding site was 27,000 vs. the delta binding site, 15,400 vs. the kappa 1 binding site, 413,700 vs the kappa 2a and 4,054 vs the kappa 2b binding site. In contrast, two other fentanyl analogs, N-(2-(4-methylpyridinyl))-N-(1-phenethyl-4-piperidinyl) 2-furamide and N-(2-pyrazinyl)-N-(1-phenethyl-4-piperdinyl)2-furamide had considerably higher Ki values at, and were less selective for, the mu binding site. Since RTI-4614-4 is composed of a mixture of four stereoisomers, the resolution of these isomers should permit identification of an extremely potent and selective agent for the opioid mu receptor.
本研究的目的是确定(+/-)-顺式-N-[1-(2-羟基-2-苯乙基)-3-甲基-4-哌啶基]-N-苯基丙酰胺盐酸盐（RTI-4614-4）对阿片受体亚型的结合亲和力，该化合物是(+)-顺式-3-甲基芬太尼的类似物。该药物对阿片受体亚型的Ki值（纳摩尔）如下：μ（0.0055）、δ（148）、κ1（84.8）、κ2a（2275）和κ2b（22.3）。该药物对μ结合位点的选择性相对于δ结合位点为27,000，相对于κ1结合位点为15,400，相对于κ2a结合位点为413,700，相对于κ2b结合位点为4,054。相比之下，另外两种芬太尼类似物，N-(2-(4-甲基吡啶基))-N-(1-苯乙基-4-哌啶基)2-呋喃酰胺和N-(2-吡嗪基)-N-(1-苯乙基-4-哌啶基)2-呋喃酰胺在μ结合位点的Ki值相当高，且对μ结合位点的选择性较低。由于RTI-4614-4由四种立体异构体的混合物组成，分离这些异构体应能鉴定出一种对阿片μ受体极具效力和选择性的药物。
