Synthesis of trans-2-[N-(2-Hydroxy-1,2,3,4-tetrahydronaphthalene-1-yl)]iminothiazolidine and Related Compounds - A New Class of Antidepressants

Antiparasitic and antidepressant activities exhibited by tetramisole (I) and its enantiomers prompted the study of its structural analogs trans-2-[N-(2-hydroxy-1,2,3,4-tetrahydronaphthalene/indane-1-yl)]iminothiazolidine (VIII/IX) and 2,3,4a,5,6,10b-hexahydronaphtho[1',2':4,5]-imidazo[2,1-b]thiazole (XII), 2,3,4a,5-tetrahydro-9bH-indeno[1',2':4,5]imidazo[2,1-b]thiazole (XIII), and 2,3,4a,5-tetrahydro-9bH-indeno[1',2':4,5]imidazo[2,1-b]thiazole (XVI), and a homolog 3,4,6,7-tetrahydro-7-phenyl-2H-imidazo[2,1-b]-1,3-thiazine (XX). While none of these compounds showed any noteworthy antiparasitic activity, the trans-2-[N-(2-hydroxy-1,2,3,4-tetrahydronaphthalene-1-yl)]iminothiazolidine (VIII) has shown marked antidepressant activity, better than imipramine in the tests used, and provides a new structural lead for antidepressants.

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An analytics-based heuristic decomposition of a bilevel multiple-follower cutting stock problem

OR Spectrum ◽

10.1007/s00291-021-00638-9 ◽

2021 ◽

Author(s):

Adejuyigbe O. Fajemisin ◽

Laura Climent ◽

Steven D. Prestwich

Keyword(s):

Real Life ◽

Forest Harvesting ◽

Cutting Stock Problem ◽

Cutting Stock ◽

Decomposition Approach ◽

New Class ◽

Bilevel Problem ◽

Programming Techniques ◽

Bilevel Problems ◽

Better Than

AbstractThis paper presents a new class of multiple-follower bilevel problems and a heuristic approach to solving them. In this new class of problems, the followers may be nonlinear, do not share constraints or variables, and are at most weakly constrained. This allows the leader variables to be partitioned among the followers. We show that current approaches for solving multiple-follower problems are unsuitable for our new class of problems and instead we propose a novel analytics-based heuristic decomposition approach. This approach uses Monte Carlo simulation and k-medoids clustering to reduce the bilevel problem to a single level, which can then be solved using integer programming techniques. The examples presented show that our approach produces better solutions and scales up better than the other approaches in the literature. Furthermore, for large problems, we combine our approach with the use of self-organising maps in place of k-medoids clustering, which significantly reduces the clustering times. Finally, we apply our approach to a real-life cutting stock problem. Here a forest harvesting problem is reformulated as a multiple-follower bilevel problem and solved using our approach.

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Structure-Activity Relationships of MDMA and Related Compounds: A New Class of Psychoactive Agents?

Topics in the Neurosciences - Ecstasy: The Clinical, Pharmacological and Neurotoxicological Effects of the Drug MDMA ◽

10.1007/978-1-4613-1485-1_7 ◽

1990 ◽

pp. 105-131 ◽

Cited By ~ 2

Author(s):

David F. Nichols ◽

Robert Oberlender

Keyword(s):

Structure Activity Relationships ◽

New Class ◽

Structure Activity ◽

Related Compounds

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Evolution and Biological Evaluation of Matrinic Derivatives with Amantadine Fragments As New Anti-Influenza Virus Agents

Molecules ◽

10.3390/molecules24050921 ◽

2019 ◽

Vol 24 (5) ◽

pp. 921 ◽

Cited By ~ 2

Author(s):

Tianyu Niu ◽

Xiaoqiang Zhao ◽

Jing Jiang ◽

Haiyan Yan ◽

Yinghong Li ◽

...

Keyword(s):

Influenza A ◽

Early Stage ◽

Biological Evaluation ◽

H3n2 Virus ◽

New Class ◽

Ic50 Values ◽

Virus Replication Cycle ◽

Sar Analysis ◽

Better Than

A series of novel tricyclic matrinic derivatives with 11-adamantyl substitution were designed, synthesized, and evaluated for their activities against Influenza A H3N2 virus, based on the privileged structure strategy. Structure-activity relationship (SAR) analysis indicated that the introduction of an 11-adamantyl might be helpful for the potency. Among them, compounds 9f and 9j exhibited the promising anti-H3N2 activities with IC50 values of 7.2 μM and 10.2 μM, respectively, better than that of lead 1. Their activities were further confirmed at the protein level. Moreover, compound 9f displayed a high pharmacokinetic (PK) stability profile in whole blood and a safety profile in vivo. In primary mechanism, compound 9f could inhibit the virus replication cycle at early stage by targeting M2 protein, consistent with that of the parent amantadine. This study provided powerful information for further strategic optimization to develop these compounds into a new class of anti-influenza agents.

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Treating Depression with SNRIs: Who Will Benefit Most?

CNS Spectrums ◽

10.1017/s1092852900028273 ◽

2008 ◽

Vol 13 (S11) ◽

pp. 15-21 ◽

Cited By ~ 3

Author(s):

Michael T. Isaac

Keyword(s):

Selective Serotonin Reuptake Inhibitors ◽

Antidepressant Medication ◽

Severe Depression ◽

Antidepressant Activity ◽

Noradrenergic System ◽

Factors Influencing ◽

Genetically Determined ◽

Norepinephrine Reuptake ◽

Better Than ◽

Cyp 2D6

AbstractThere is evidence that the serotonin norepinephrine reuptake inhibitors (SNRIs) venlafaxine, milnacipran, and duloxetine, have probable superior antidepressant activity to most selective serotonin reuptake inhibitors (SSRIs), especially in more severe depression. Some patients, however, respond better than others to SNRIs. Several factors influencing response to milnacipran have been recently studied. The presence of certain polymorphisms related to noradrenergic neurotransmission has been shown to be related to different degrees or rapidity of response to milnacipran. In addition, patients with low pretreatment levels of plasma 3-methoxy-4-hydroxyphenylglycol have a better response to milnacipran. These recent genomic and neurochemical data confirm that milnacipran, in contrast to SSRIs and venlafaxine, has an impact on the noradrenergic system. Differences in metabolism determined by genetic variables in cytochrome P450 (CYP) 2D6 activity are a major determinant of venlafaxine levels to such an extent that genetically determined decreases in CYP 2D6 activity have been associated increased adverse effects. Milnacipran, which is not metabolized by the enzymes of the CYP system is not influenced by polymorphism of these enzymes. These preliminary data suggest that a patient's biochemical and pharmacogenetic characteristics may be useful in the future to help clinicians chose the most effective antidepressant medication.

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Synthesis and antiviral/antitumor evaluation of 2-amino- and 2-carboxamido-3-arylsulfonylthiophenes and related compounds as a new class of diarylsulfones

Bioorganic & Medicinal Chemistry ◽

10.1016/s0968-0896(00)00333-3 ◽

2001 ◽

Vol 9 (5) ◽

pp. 1123-1132 ◽

Cited By ~ 40

Author(s):

C Stephens

Keyword(s):

New Class ◽

Related Compounds ◽

Antitumor Evaluation

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Everyday Problems in Treating Depression: Focus on SNRIs

CNS Spectrums ◽

10.1017/s1092852900028248 ◽

2008 ◽

Vol 13 (S11) ◽

pp. 4-4 ◽

Cited By ~ 1

Author(s):

Siegfried Kasper

Keyword(s):

Selective Serotonin Reuptake Inhibitors ◽

Antidepressant Activity ◽

New Class ◽

Treatment Of Depression ◽

Norepinephrine Reuptake Inhibitor ◽

Dual Action ◽

Everyday Problems ◽

Serotonin Norepinephrine Reuptake Inhibitor ◽

Poor Tolerability ◽

Norepinephrine Reuptake

Most effective antidepressants directly or indirectly increase the synaptic concentrations of serotonin (5-HT) and/or norepinephrine (NE) by blocking the reuptake of one or both of the neurotransmitters. This property was initially discovered with the tricyclic antidepressants (TCAs). Their various additional interactions at different receptors and ion channels are not required for antidepressant action, but are responsible for the poor tolerability and toxicity in overdose of the early antidepressants.The selective serotonin reuptake inhibitors are effective and well tolerated. Selective norepinephrine reuptake inhibitors, such as reboxetine, also have proven antidepressant activity. A selective action on one or the other of the principal monoamines thus appears to be sufficient for antidepressant activity. The idea that a dual action on both neurotransmitters might produce greater efficacy in certain patients led to the development of the serotonin norepinephrine reuptake inhibitor (SNRI) antidepressants, which block the reuptake of both 5-HT and NE without the nonspecific, side-effect–inducing interactions of the TCAs. The three SNRIs—venlafaxine, milnacipran, and duloxetine—constitute a new class of antidepressants.Antidepressant response rates rarely exceed 60% to 70% and remission rates are usually <50%. Although SNRIs clearly provide superior efficacy in certain populations, their use has not dramatically changed antidepressant therapy. The search for agents that are more effective, rapidly acting, and better tolerated continues. However, clinicians must find ways to better use the antidepressants that are available today. This supplement, based on a symposium held at the International Forum on Affective Disorders in Budapest in December 2007, discusses several everyday problems in the treatment of depression, with a focus on SNRIs.

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