title: Synthesis and pharmacological studies of new hybrid derivatives of fentanyl active at the mu-opioid receptor and I2-imidazoline binding sites.
abstract: Two series of fentanyl-derived hybrid molecules bearing potent I2-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 I2-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 I2-IBS in the micromolar to low micromolar range, the alkaneguanidine series exhibited remarkable affinities in the nanomolar range for both receptors. [35S]GTPgammaS 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 I2-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 (Ki mu=1.04+/-0.28 nM, Ki I2=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 (Ki=0.0098+/-0.0033 nM), whereas 13 presented an I2-IBS affinity (Ki=18+/-11 nM) similar to the reference compound BU224.
authors.affiliation: Instituto de Química Médica, CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain. dardonville@iqm.csic.es
authors.forename: Christophe
authors.initials: C
authors.lastname: Dardonville
authors.forename: Cristina
authors.initials: C
authors.lastname: Fernandez-Fernandez
authors.forename: Sarah-Louise
authors.initials: SL
authors.lastname: Gibbons
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Ryan
authors.forename: Nadine
authors.initials: N
authors.lastname: Jagerovic
authors.forename: Ane M
authors.initials: AM
authors.lastname: Gabilondo
authors.forename: J Javier
authors.initials: JJ
authors.lastname: Meana
authors.forename: Luis F
authors.initials: LF
authors.lastname: Callado
mesh_terms: D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D005283:Fentanyl / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019791:Guanidine / Q000737:chemistry; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D054755:Imidazoline Receptors; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008297:Male; D008566:Membranes / Q000378:metabolism; D051379:Mice; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011930:Reaction Time / Q000187:drug effects; D011955:Receptors, Drug / Q000187:drug effects*; D017450:Receptors, Opioid, mu / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000701:Analgesics, Opioid; D054755:Imidazoline Receptors; D007202:Indicators and Reagents; D009292:Narcotic Antagonists; D011955:Receptors, Drug; D017450:Receptors, Opioid, mu; C487767:imidazoline receptor 2; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009270:Naloxone; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D019791:Guanidine; D005283:Fentanyl