title: Novel fluoroalkyl derivatives of selective kappa opioid receptor antagonist JDTic: Design, synthesis, pharmacology and molecular modeling studies.
abstract: Novel N- and O-fluoroalkyl derivatives of the highly potent KOR antagonist JDTic were designed and synthesized. Their opioid receptor properties were compared in both in vitro binding assays and modeling approach. All compounds displayed nanomolar affinities for KOR. The fluoropropyl derivatives were more active than their fluoroethyl analogues. N-Fluoroalkylation was preferable to O-alkylation to keep a selective KOR binding. Compared to JDTic, the N-fluoropropyl derivative 2 bound to KOR with an only 4-fold lower affinity and a higher selectivity relative to MOR and DOR [Ki(κ) = 1.6 nM; Ki(μ)/Ki(κ) = 12; Ki(δ)/Ki(κ) = 159 for 2versus Ki(κ) = 0.42 nM; Ki(μ)/Ki(κ) = 9; Ki(δ)/Ki(κ) = 85 for JDTic]. Modeling studies based on the crystal structure of the JDTic/KOR complex revealed that fluorine atom in ligand 2 was involved in specific KOR binding. Ligand 2 was concluded to merit further development for KOR exploration.
authors.affiliation: CNRS, UMR 6301 ISTCT, LDM-TEP, GIP CYCERON, Boulevard Henri Becquerel, 14074 Caen, France; Université de Caen Basse-Normandie, Normandie Univ., France; CEA, DSV/I2BM, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Schmitt
authors.affiliation: Université de Caen Basse-Normandie, Normandie Univ., France; CEA, DSV/I2BM, France; CNRS, UMR 6301 ISTCT, CERVOxy group, GIP CYCERON, Boulevard Henri Becquerel, 14074 Caen, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Colloc'h
authors.affiliation: CNRS, UMR 6301 ISTCT, LDM-TEP, GIP CYCERON, Boulevard Henri Becquerel, 14074 Caen, France; Université de Caen Basse-Normandie, Normandie Univ., France; CEA, DSV/I2BM, France. Electronic address: perrio@cyceron.fr.
authors.forename: Cécile
authors.initials: C
authors.lastname: Perrio
mesh_terms: D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D006845:Hydrocarbons, Fluorinated; D017473:Receptors, Opioid, kappa; D044005:Tetrahydroisoquinolines
keywords: (3R,4R)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine; Docking; JDTic; Kappa opioid receptor; Selectivity