56225-81-1Relevant articles and documents
An azetidinium ion approach to 3-aryloxy-3-aryl-1-propanamines
O'Brien, Peter,Phillips, David W.,Towers, Timothy D.
, p. 7333 - 7335 (2002)
Treatment of 3-(dimethylamino)-1-phenyl-propan-1-ol with mesyl chloride and then different phenols generates a range of N,N-dimethyl-3-aryloxy-3-aryl-1-propanamines via regiospecific opening of a proposed azetidinium ion intermediate. During the rearrangement process, there was some leakage of stereochemical integrity.
B(C6F5)3-Catalyzed C-H Alkylation of N-Alkylamines Using Silicon Enolates without External Oxidant
Chan, Jessica Z.,Chang, Yejin,Wasa, Masayuki
supporting information, p. 984 - 988 (2019/02/14)
An efficient method for the coupling of N-alkylamines with silicon enolates to generate β-amino carbonyl compounds is disclosed. These reactions proceed by activation of α-amino C-H bonds by B(C6F5)3, which likely generate
Derivatization of common antidepressant drugs increases inhibition of acid sphingomyelinase and reduces induction of phospholipidosis
Rhein, Cosima,L?ber, Stefan,Gmeiner, Peter,Gulbins, Erich,Tripal, Philipp,Kornhuber, Johannes
, p. 1837 - 1845 (2018/09/12)
In recent studies, major depressive disorder (MDD) was linked to an increase in acid sphingomyelinase (ASM) activity. Several drugs that are commonly used to treat MDD functionally inhibit the lysosomal enzyme ASM and are called functional inhibitors of ASM (FIASMAs). These drugs are classified as cationic amphiphilic drugs (CADs) that influence the catalytic activities of different lysosomal enzymes. This action results in the side effect of phospholipidosis (PLD), which describes a detrimental increase in the phospholipid content in lysosomes. FIASMAs differ only slightly in their physico-chemical properties, but their effects on ASM activity and induction of the lysosomal phospholipid content vary significantly. In this study, we systematically induced minor chemical modifications to the FIASMAs imipramine, desipramine and fluoxetine. We generated a library of 45 new CADs with slightly different log P (logarithmic partition coefficient) and pKa (logarithmic acid dissociation constant) values. The effects of the compounds on the ASM activity and lysosomal phospholipid content were assessed in cell culture assays. We identified four compounds with beneficial effects, i.e., increased ASM activity inhibition and reduced PLD induction compared with the original drugs. The compounds HT04, RH272B and RH272D outperformed the original imipramine, whereas RH281A performed better than desipramine. Thus, minor chemical variations of CADs impact lysosomal metabolism in a specific manner and can lead to antidepressant drugs with less deleterious side effects.
Molecular basis for selective serotonin reuptake inhibition by the antidepressant agent fluoxetine (Prozac)
Andersen, Jacob,Stuhr-Hansen, Nicolai,Zachariassen, Linda Gronborg,Koldso, Heidi,Schiott, Birgit,Stromgaard, Kristian,Kristensen, Anders S.
, p. 703 - 714 (2014/04/17)
Inhibitors of the serotonin transporter (SERT) are widely used antidepressant agents, but the structural mechanism for inhibitory activity and selectivity over the closely related norepinephrine transporter (NET) is not well understood. Here we use a combination of chemical, biological, and computational methods to decipher the molecular basis for high-affinity recognition in SERT and selectivity over NET for the prototypical antidepressant drug fluoxetine (Prozac; Eli Lilly, Indianapolis, IN). We show that fluoxetine binds within the central substrate site of human SERT, in agreement with recent X-ray crystal structures of LeuBAT, an engineered monoamine-like version of the bacterial amino acid transporter LeuT. However, the binding orientation of fluoxetine is reversed in our experimentally supported model comparedwith the LeuBAT structures, emphasizing the need for careful experimental verification when extrapolating findings from crystal structures of bacterial transporters to human relatives. We find that the selectivity of fluoxetine and nisoxetine, a NET selective structural congener of fluoxetine, is controlled by residues in different regions of the transporters, indicating a complex mechanism for selective recognition of structurally similar compounds in SERT and NET. Our findings add important new information on the molecular basis for SERT/NET selectivity of antidepressants, and provide the first assessment of the potential of LeuBAT as a model system for antidepressant binding in human transporters, which is essential for future structure-based drug development of antidepressant drugs with fine-tuned transporter selectivity. Copyright
Pulmonary delivery for bioconjugation
-
, (2008/06/13)
Methods of and compositions for pulmonary delivery of therapeutic agents which are capable of forming covalent bonds with a site of interest or which have formed a covalent bond with a pulmonary solution protein are disclosed. Therapeutic agents useful in the invention include wound healing agents, antibiotics, anti-inflammatories, anti-oxidants, anti-proliferatives, immunosupressants, anti-infective and anti-cancer agents.
Treatment of obesity with aryloxyphenylpropylamines
-
, (2008/06/13)
3-Aryloxy-3-phenylpropylamines and acid addition salts thereof are useful in blocking uptake of monoamines by brain neurons, and are thus effective in treating disorders of sleep, sexual performance, appetite, muscular function, and pituitary function.
Aryloxyphenylpropylamines in treating depression
-
, (2008/06/13)
3-Aryloxy-3-phenylpropylamines and acid additions salts thereof, useful as psychotropic agents, particularly as anti-depressants.
