Synthesis and pharmacological studies of new hybrid derivatives of fentanyl active at the mu -opioid receptor and I sub(2)-imidazoline binding sites

• Published in: Bioorganic & medicinal chemistry Vol. 14; no. 19; pp. 6570 - 6580
• Main Authors: Dardonville, Christophe, Fernandez-Fernandez, Cristina, Gibbons, Sarah-Louise, Ryan, Gary J, Jagerovic, Nadine, Gabilondo, Ane M, Meana, JJavier, Callado, Luis F
• Format: Journal Article
• Language: English
• Published: 01-10-2006
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2006.06.007

Two series of fentanyl-derived hybrid molecules bearing potent I sub(2)- imidazoline binding site (IBS) ligands (i.e., guanidine and BU224 moieties) linked with an aliphatic (m = 2, 3, 4, 6, 7, 8, 9 and 12 methylene units) or aromatic spacer were prepared. Their affinities for the mu -opioid receptors and for the I sub(2)-IBS were determined through competition binding studies on human postmortem brain membranes. Whereas the BU224 hybrid molecules bound to the mu - opioid receptor and the I sub(2)-IBS in the micromolar to low micromolar range, the alkaneguanidine series exhibited remarkable affinities in the nanomolar range for both receptors. [ super(35)S]GTP gamma S functional assays were performed on human postmortem brain membranes with selected ligands from each series (4f and 8g) showing the highest dual affinity for the mu -opioid receptor and I sub(2)-IBS affinities. Both compounds displayed agonist properties: at the mu -opioid receptor for the alkaneguanidine derivative 4f (spacer: six methylene units) and at a G-protein coupled receptor (GPCR) which remains to be determined for 8g. The lack of analgesic properties of 4f in vivo (i.e., hot plate and writhing tests in mice), discordant with the good in vitro binding data (K sub(i) mu = 1.04 +/- 0.28 nM, K sub(i) I sub(2) = 409 +/- 238 nM), may possibly be due to the low intrinsic efficacy of the compound. Alternatively, a low access to the central nervous system for this kind of hybrid molecules cannot be ruled out. Two new compounds reported here (9f and 13), which were not dual acting, are worth mentioning for their outstanding binding affinities; 9f bound to the mu -opioid receptor with a picomolar affinity (K sub(i) = 0.0098 +/- 0.0033 nM), whereas 13 presented an I sub(2)-IBS affinity (K sub(i) = 18 +/- 11 nM) similar to the reference compound BU224.