439099-20-4Relevant articles and documents
Synthesis and pharmacological studies of new hybrid derivatives of fentanyl active at the μ-opioid receptor and I2-imidazoline binding sites
Dardonville, Christophe,Fernandez-Fernandez, Cristina,Gibbons, Sarah-Louise,Ryan, Gary J.,Jagerovic, Nadine,Gabilondo, Ane M.,Meana, J. Javier,Callado, Luis F.
, p. 6570 - 6580 (2007/10/03)
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 μ-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 μ-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]GTPγS 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 μ-opioid receptor and I2-IBS affinities. Both compounds displayed agonist properties: at the μ-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 μ = 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 μ-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.
Guanidinium and aminoimidazolinium derivatives of N-(4-piperidyl)propanamides as potential ligands for μ opioid and I2-imidazoline receptors: Synthesis and pharmacological screening
Montero, Ana,Goya, Pilar,Jagerovic, Nadine,Callado, Luis F,Meana,Giron, Rocio,Goicoechea, Carlos,Martin, M Isabel
, p. 1009 - 1018 (2007/10/03)
Derivatives of N-(1-phenethyl-4-piperidyl)propanamides incorporating guanidinium and 2-aminoimidazolinium groups have been prepared by a synthetic approach involving first introduction of a spacer between the piperidine and the functional group by reductive amination of piperidinone. The formation of each of these functional groups was carried out using N-N′ -di(tert-butoxycarbonyl) thiourea and 2-methylthioimidazolinium iodide, respectively. These structures have been designed to incorporate two pharmacologic goals into one entity. Radioligand binding assays ave been used to study their affinity for opioid (μ δ and κ) and I 2 -imidazoline receptors. Two of them, 10 and 16, showed high affinity for μ opioid receptors and functionally they had moderate analgesic properties in the hot plate and writhing tests. The in vitro studies on guinea pig ileum (GPI) indicated that both compounds are μ opioid agonists. In what concerns I2 -imidazoline receptor activity, these derivatives showed low affinity around 6 to 7 times less than idazoxan. Copyright
