ABSTRACT
The synthesis and SAR of a series of chiral heterocyclic ring-constrained norepinephrine reuptake inhibitors are described. The best compounds compare favorably with atomoxetine in potency (IC(50)s<10 nM), selectivity against the other monoamine transporters, and inhibition of CYP2D6 (IC(50)s>1 microM). In addition, the compounds are generally more stable than atomoxetine to oxidative metabolism and thus are likely to have lower clearance in humans.
Subject(s)
Adrenergic Uptake Inhibitors/chemical synthesis , Adrenergic Uptake Inhibitors/pharmacology , Chemistry, Pharmaceutical/methods , Norepinephrine Plasma Membrane Transport Proteins/chemical synthesis , Norepinephrine Plasma Membrane Transport Proteins/pharmacology , Norepinephrine/chemistry , Oxygen/chemistry , Adrenergic Uptake Inhibitors/chemistry , Atomoxetine Hydrochloride , Cytochrome P-450 CYP2D6/chemistry , Drug Design , Humans , Inhibitory Concentration 50 , Models, Chemical , Molecular Conformation , Norepinephrine/metabolism , Propylamines/chemistry , Propylamines/pharmacology , Structure-Activity Relationship , Symporters/chemistryABSTRACT
The design, synthesis, and SAR of a series of ring-constrained norepinephrine reuptake inhibitors are described. A substantially rigid inhibitor with potent functional activity at the transporter (IC(50)=8 nM) was used to develop a model for the distance and orientation of key features necessary for interaction with the norepinephrine transporter (NET).
Subject(s)
Adrenergic Uptake Inhibitors/chemical synthesis , Adrenergic Uptake Inhibitors/pharmacology , Norepinephrine Plasma Membrane Transport Proteins/chemical synthesis , Norepinephrine Plasma Membrane Transport Proteins/pharmacology , Amines/chemistry , Atomoxetine Hydrochloride , Binding Sites , Cell Line , Chemistry, Pharmaceutical/methods , Desipramine/chemistry , Drug Design , Humans , Inhibitory Concentration 50 , Models, Chemical , Molecular Conformation , Propylamines/chemistry , Structure-Activity RelationshipABSTRACT
Desipramine (DMI), talopram and talsupram, three of the most potent norepinephrine transporter (NET) inhibitors reported to date, were radiolabeled in high yields and at high specific radioactivity (58-75 GBq/micromol) by the methylation of nor-precursors with [C-11]methyl triflate. The regional brain distribution of each radioligand following intravenous injection into cynomolgus monkey was examined in vivo with positron emission tomography (PET). For all three radioligands, the regional brain distribution of radioactivity was slightly heterogeneous, with higher uptake of radioactivity in the mesencephalon, thalamus and lower brainstem than in striatum. The rank order of maximal brain radioactivity (as percentage of injected dose) was [C-11]DMI (2.7%) > [C-11]talsupram (1.3%) > [C-11]talopram (0.7%). The appearance of radioactive metabolites in plasma was similar for each radioligand (75-85% of radioactivity in plasma at 45 min). These metabolites were all more polar than their parent radioligand. The data show that these radioligands are inferior to existing radioligands for the study of brain NET with PET in vivo.
