title: 'Carba'-carfentanil (trans isomer): a μ opioid receptor (MOR) partial agonist with a distinct binding mode.
abstract: There is strong evidence to indicate that a positively charged nitrogen of endogenous and exogenous opioid ligands forms a salt bridge with the Asp residue in the third transmembrane helix of opioid receptors. To further examine the role of this electrostatic interaction in opioid receptor binding and activation, we synthesized 'carba'-analogues of the highly potent μ opioid analgesic carfentanil (3), in which the piperidine nitrogen was replaced with a carbon. The resulting trans isomer (8b) showed reduced, but still significant MOR binding affinity (Ki(μ)=95.2nM) with no MOR versus DOR binding selectivity and was a MOR partial agonist. The cis isomer (8a) was essentially inactive. A MOR docking study indicated that 8b bound to the same binding pocket as parent 3, but its binding mode was somewhat different. A re-evaluation of the uncharged morphine derivative N-formylnormorphine (9) indicated that it was a weak MOR antagonist showing no preference for MOR over KOR. Taken together, the results indicate that deletion of the positively charged nitrogen in μ opioid analgesics reduces MOR binding affinity by 2-3 orders of magnitude and may have pronounced effects on the intrinsic efficacy and on the opioid receptor selectivity profile.
authors.affiliation: Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, QC H2W 1R7, Canada.
authors.forename: Grazyna
authors.initials: G
authors.lastname: Weltrowska
authors.affiliation: Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, QC H2W 1R7, Canada.
authors.forename: Carole
authors.initials: C
authors.lastname: Lemieux
authors.affiliation: Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, QC H2W 1R7, Canada.
authors.forename: Nga N
authors.initials: NN
authors.lastname: Chung
authors.affiliation: Center for Drug Discovery, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Guo
authors.affiliation: Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, QC H2W 1R7, Canada.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Wilkes
authors.affiliation: Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, QC H2W 1R7, Canada; Department of Pharmacology, Université de Montréal, Montreal, QC H3C 3J7, Canada. Electronic address: schillp@ircm.qc.ca.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Schiller
mesh_terms: D004305:Dose-Response Relationship, Drug; D005283:Fentanyl / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D017450:Receptors, Opioid, mu; C017114:carfentanil; D005283:Fentanyl
keywords: Carfentanil; Opioid activity profiles; μ opioid receptor binding mode; ‘Carba’-carfentanil