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.
Keywords: (3R,4R)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine; Docking; JDTic; Kappa opioid receptor; Selectivity.
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