ABSTRACT
Atypical dopamine reuptake inhibitors, such as modafinil, are used for the treatment of sleeping disorders and investigated as potential therapeutics against cocaine addiction and for cognitive enhancement. Our continuous effort to find modafinil analogues with higher inhibitory activity on and selectivity toward the dopamine transporter (DAT) has previously led to the promising thiazole-containing derivatives CE-103, CE-111, CE-123, and CE-125. Here, we describe the synthesis and activity of a series of compounds based on these scaffolds, which resulted in several new selective DAT inhibitors and gave valuable insights into the structure-activity relationships. Introduction of the second chiral center and subsequent chiral separations provided all four stereoisomers, whereby the S-configuration on both generally exerted the highest activity and selectivity on DAT. The representative compound of this series was further characterized by in silico, in vitro, and in vivo studies that have demonstrated both safety and efficacy profile of this compound class.
Subject(s)
Dopamine Plasma Membrane Transport Proteins/antagonists & inhibitors , Dopamine Uptake Inhibitors/pharmacology , Modafinil/analogs & derivatives , Modafinil/pharmacology , Serotonin and Noradrenaline Reuptake Inhibitors/pharmacology , Thiazoles/pharmacology , Animals , Dopamine Plasma Membrane Transport Proteins/metabolism , Dopamine Uptake Inhibitors/chemical synthesis , Dopamine Uptake Inhibitors/metabolism , Dopamine Uptake Inhibitors/pharmacokinetics , HEK293 Cells , Humans , Male , Modafinil/metabolism , Modafinil/pharmacokinetics , Molecular Docking Simulation , Molecular Structure , Norepinephrine Plasma Membrane Transport Proteins/antagonists & inhibitors , Protein Binding , Rats, Sprague-Dawley , Serotonin Plasma Membrane Transport Proteins/metabolism , Serotonin and Noradrenaline Reuptake Inhibitors/chemical synthesis , Serotonin and Noradrenaline Reuptake Inhibitors/metabolism , Serotonin and Noradrenaline Reuptake Inhibitors/pharmacokinetics , Stereoisomerism , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/metabolism , Thiazoles/pharmacokineticsABSTRACT
Modafinil is a wake promoting compound with high potential for cognitive enhancement. It is targeting the dopamine transporter (DAT) with moderate selectivity, thereby leading to reuptake inhibition and increased dopamine levels in the synaptic cleft. A series of modafinil analogues have been reported so far, but more target-specific analogues remain to be discovered. It was the aim of this study to synthesize and characterize such analogues and, indeed, a series of compounds were showing higher activities on the DAT and a higher selectivity toward DAT versus serotonin and norepinephrine transporters than modafinil. This was achieved by substituting the amide moiety by five- and six-membered aromatic heterocycles. In vitro studies indicated binding to the cocaine pocket on DAT, although molecular dynamics revealed binding different from that of cocaine. Moreover, no release of dopamine was observed, ruling out amphetamine-like effects. The absence of neurotoxicity of a representative analogue may encourage further preclinical studies of the above-mentioned compounds.
Subject(s)
Benzhydryl Compounds/pharmacology , Dopamine Plasma Membrane Transport Proteins/antagonists & inhibitors , Dopamine Uptake Inhibitors/pharmacology , Heterocyclic Compounds/pharmacology , 1-Methyl-4-phenylpyridinium/metabolism , Animals , Benzhydryl Compounds/chemical synthesis , Binding Sites , Dopamine/metabolism , Dopamine Uptake Inhibitors/chemical synthesis , HEK293 Cells , Heterocyclic Compounds/chemical synthesis , Humans , Male , Modafinil , Molecular Docking Simulation , Molecular Dynamics Simulation , Norepinephrine Plasma Membrane Transport Proteins/antagonists & inhibitors , Rats, Sprague-Dawley , Serotonin and Noradrenaline Reuptake Inhibitors/chemical synthesis , Serotonin and Noradrenaline Reuptake Inhibitors/pharmacology , Structure-Activity Relationship , Sulfoxides/chemical synthesis , Sulfoxides/pharmacology , Thiophenes/chemical synthesis , Thiophenes/pharmacologyABSTRACT
A series of 4-benzylpiperidine carboxamides were designed and synthesized, and tested for their dual (serotonin and norepinephrine) reuptake inhibition. The synthesis of 4-benzylpiperidine carboxamides involved two main steps: amidation and substitution. Derivatives with 3 carbon linker displayed better activity than with 2 carbon linker. 4-Biphenyl- and 2-naphthyl-substituted derivatives 7e and 7j showed greater dual reuptake inhibition than standard drug venlafaxine HCl.
Subject(s)
Amides/chemistry , Drug Design , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Serotonin and Noradrenaline Reuptake Inhibitors/chemical synthesis , Amides/chemical synthesis , Amides/metabolism , HEK293 Cells , Humans , Norepinephrine Plasma Membrane Transport Proteins/chemistry , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Piperidines/chemistry , Protein Binding , Serotonin Plasma Membrane Transport Proteins/chemistry , Serotonin Plasma Membrane Transport Proteins/metabolism , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/metabolism , Serotonin and Noradrenaline Reuptake Inhibitors/chemistry , Serotonin and Noradrenaline Reuptake Inhibitors/metabolism , Structure-Activity RelationshipABSTRACT
Centrally acting noradrenaline reuptake inhibitor (NRI) is reportedly effective for patients with stress urinary incontinence (SUI) by increasing urethral closure in the clinical Phase IIa study with esreboxetine. Noradrenaline transporters are expressed in both central and peripheral nervous systems and the contribution of each site to efficacy has not been clarified. This report describes the development of a series of peripheral-selective 7-phenyl-1,4-oxazepane NRIs to investigate the contribution of the peripheral site to increasing urethral resistance in rats. (6S,7R)-1,4-Oxazepane derivative 7 exhibited noradrenaline transporter inhibition with high selectivity against inhibitions of serotonin and dopamine transporters. A replacement of hydroxyl with acetamide group contributed to enhancement of peripheral selectivity by increasing molecular polarity. Compound 12, N-{[(6S,7R)-7-(3,4-dichlorophenyl)-1,4-oxazepan-6-yl]methyl}acetamide 0.5 fumarate, which showed effectively no brain penetration in rats, increased urethral resistance in a dose-dependent manner and exhibited a maximal effect on par with esreboxetine. These results demonstrate that the urethral resistance-increasing effects of NRI in rats are mainly caused by the inhibition of noradrenaline transporters in the peripheral sites.
