RTI-4614-4: An Analog of (+)-cis-3-Methylfentanyl with a 27,000-fold Binding Selectivity for Mu Versus Delta Opioid Binding Sites
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-HCl (RTl-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), kappa1 (84.8), kappa2a (2275), and kappa2b (22.3). The selectivity of this agent for the mu binding site was 27,000 vs. the delta binding site, 15,400 vs. the kappa1 binding site, 413,700 vs the kappa2a and 4,054 vs the kappa2b 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 RTl-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.
Rothman, RB., Xu, H., Seggel, M., Jacobson, A. E., Rice, K. C., Brine, G., & Carroll, F. (1991). RTI-4614-4: An Analog of (+)-cis-3-Methylfentanyl with a 27,000-fold Binding Selectivity for Mu Versus Delta Opioid Binding Sites. Life Sciences, 48(23), PL111-PL116. DOI: 10.1016/0024-3205(91)90346-D