Synthesis and activity of novel 1- or 3-(3-amino-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors (original) (raw)
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Bioorganic & Medicinal Chemistry Letters, 2009
Serotonin and norepinephrine reuptake inhibitors SNRI Norepinephrine reuptake inhibitors NRI Serotonin reuptake inhibitor SRI Monoamine reuptake inhibitors a b s t r a c t A series of 3-(arylamino)-3-phenylpropan-2-olamines was prepared and screened for their ability to inhibit monoamine reuptake. A number of analogues displayed significant dual norepinephrine and serotonin reuptake inhibition. Compounds in this class exhibited minimal affinity for the dopamine transporter.
Bioorganic & Medicinal Chemistry Letters, 2011
The current work discloses a novel cyclohexylarylamine chemotype with potent inhibition of the serotonin, norepinephrine, and dopamine transporters and potential for treatment of major depressive disorder. Optimized compounds 1 (SERT, NET, DAT, IC 50 = 169, 85, 21 nM) and 42 (SERT, NET, DAT IC 50 = 34, 295, 90 nM) were highly brain penetrant, active in vivo in the mouse tail suspension test at 30 mpk po and were not general motor stimulants.
Neuropsychopharmacologia Hungarica, 2020
Discovery and development of the selective serotonin reuptake inhibitors mark a milestone in neuro-pharmacology. Drugs from this class alter the functioning of the serotonin system by the potentiation of serotonin through the negative allosteric modulation of its neuronal uptake by the human serotonin transporter. Selective serotonin reuptake inhibitors show few side effects compared to those caused by traditional antidepressants and they vary in the binding interactions formed during binding. Gener-ally, their binding involves three specific regions of the drug structures, each participating in vital inter-actions, such as salt bridge formation and additional hydrophobic interactions with conserved resi-dues in the central binding site of the target protein. Side effects, however, such as the initial lack of response to treatment, or drowsiness, nausea, and sexual dysfunction occasionally may arise. Addi-tional binding studies, furthermore, highlighted the importance of enantioselectivity in the binding of these compounds, raising concerns about the beneficial application of racemate mixtures of some of these compounds. Therefore, additional characterisation of binding and further structural improve-ment of this class of drugs is necessary. The recently synthesized sertraline salts, and functional deriv-atives of fluoxetine and citalopram show promising results in delivering antidepressant activity as well as in effectively overcoming anorexigenic side-effects in rodent models. Hence, despite certain non-desired effects associated with selective serotonin reuptake inhibitor applications, this class of drugs is considered as first-line medication in the management of major depression, and is carrying an excel-lent potential for the development and refinement of the currently available and novel antidepressant therapies.
Bioorganic & Medicinal Chemistry Letters, 2011
Novel chiral cyclohexylaryl amines were developed with potent reuptake inhibition against the serotonin, norepinephrine and dopamine transporters and activity at 10 and 30 mpk PO in the mouse tail suspension test. Prototype compound 31 (SERT, NET, DAT IC 50 6 1, 21, 28 nM) was highly brain penetrant, had minimal CYP and hERG inhibition, and represents a previously undisclosed architecture with potential for treatment of major depressive disorder.
Bioorganic & Medicinal Chemistry Letters, 1998
A series of gamma-amino alcohols were synthesized and screened for reuptake inhibition and noncompetitive NMDA antagonism. Compound (+)-3f simultaneously and potently inhibits reuptake of 5-HT, NE, and DA, representing a potential wide-spectrum reuptake inhibitor antidepressant. In addition, comparative rat and human studies uncovered a species-selective DA reuptake inhibitor (+)-2e, KD(hDAT)/KD(rDAT) = 97. The past 20 years have seen the development of selective serotonin (5-HT)-reuptake inhibitor (SSRI) antidepressants (e.g. fluoxetine, paroxetine, and sertaline) and selective norepinephrine (NE)-reuptake inhibitor antidepressants (e.g. tomoxetine and viloxazine) (Scheme 1). In addition, drugs which inhibit rat synaptosomal 5-HT-and NE-reuptake with similar potency (SNRI antidepressants, e.g. venlafaxine, nefazodone) have also been developed.l Examination of the structures of all these reuptake inhibiting antidepressants indicates that a number of them possess the gamma-amino ether or gamma-amino alcohol functional group (Scheme 1).
Discovery of a Potent, Dual Serotonin and Norepinephrine Reuptake Inhibitor
ACS Medicinal Chemistry Letters, 2013
The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable metabolic stability and exhibiting minimal drugādrug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Compound 1 is a selective SNRI in vitro and in vivo, has favorable ADME properties, and retains inhibitory activity in the formalin model of pain behavior. Compound 1 thus represents a potential new probe to explore utility of SNRIs in central nervous system disorders, including chronic pain conditions.