Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 10 de 10
Filter
Add more filters










Publication year range
1.
Bioorg Med Chem ; 21(11): 3164-74, 2013 Jun 01.
Article in English | MEDLINE | ID: mdl-23623679

ABSTRACT

The goal of the present study was to explore, in our previously developed hybrid template, the effect of introduction of additional heterocyclic rings (mimicking catechol hydroxyl groups as bioisosteric replacement) on selectivity and affinity for the D3 versus D2 receptor. In addition, we wanted to explore the effect of derivatization of functional groups of the agonist binding moiety in compounds developed by us earlier from the hybrid template. Binding affinity (K(i)) of the new compounds was measured with tritiated spiperone as the radioligand and HEK-293 cells expressing either D2 or D3 receptors. Functional activity of selected compounds was assessed in the GTPγS binding assay. In the imidazole series, compound 10a exhibited the highest D3 affinity whereas the indole derivative 13 exhibited similar high D3 affinity. Functionalization of the amino group in agonist (+)-9d with different sulfonamides derivatives improved the D3 affinity significantly with (+)-14f exhibiting the highest affinity. However, functionalization of the hydroxyl and amino groups of 15 and (+)-9d, known agonist and partial agonist, to sulfonate ester and amide in general modulated the affinity. In both cases loss of agonist potency resulted from such derivatization.


Subject(s)
Dopamine Agonists/chemical synthesis , Naphthalenes/chemical synthesis , Piperazines/chemical synthesis , Receptors, Dopamine D2/agonists , Receptors, Dopamine D3/agonists , Animals , CHO Cells , Cricetulus , Dopamine Agonists/chemistry , Guanosine 5'-O-(3-Thiotriphosphate)/chemistry , HEK293 Cells , Humans , Kinetics , Naphthalenes/chemistry , Piperazines/chemistry , Protein Binding , Radioligand Assay , Receptors, Dopamine D2/chemistry , Receptors, Dopamine D3/chemistry , Spiperone/chemistry , Structure-Activity Relationship
2.
ChemMedChem ; 7(12): 2093-100, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23060293

ABSTRACT

To further explore the basic structural motifs (3S,6S)-6-benzhydryl-N-benzyltetrahydro-2H-pyran-3-amine and (2S,4R,5R)-2-benzhydryl-5-(benzylamino)tetrahydro-2H-pyran-4-ol, developed by our research group, for monoamine transport inhibition, we designed and synthesized various structurally altered analogues. The new compounds were tested for their affinities for the dopamine transporter (DAT), the serotonin transporter (SERT), and the norepinephrine transporter (NET) in rat brain by measuring their capacity to inhibit the uptake of [(3)H]DA, [(3)H]5-HT, and [(3)H]NE, respectively. Our results point to novel compounds with a TUI, DNRI, SNRI, or SSRI profile. Among the TUIs, compound 2 g exhibited a balanced potency for all three monoamine transporters (K(i): 60, 79, and 70.3 nM for DAT, SERT, and NET, respectively). In the rat forced swim test, compound 2 g produced a significant decrease in immobility in drug-treated rats relative to vehicle, indicating a potential antidepressant property.


Subject(s)
Antidepressive Agents/chemistry , Antidepressive Agents/pharmacology , Neurotransmitter Uptake Inhibitors/chemistry , Neurotransmitter Uptake Inhibitors/pharmacology , Pyrans/chemistry , Pyrans/pharmacology , Animals , Brain/drug effects , Brain/metabolism , Dopamine Plasma Membrane Transport Proteins/antagonists & inhibitors , Dopamine Plasma Membrane Transport Proteins/metabolism , Male , Motor Activity/drug effects , Norepinephrine/metabolism , Norepinephrine Plasma Membrane Transport Proteins/antagonists & inhibitors , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Rats , Rats, Sprague-Dawley , Serotonin/metabolism , Serotonin Plasma Membrane Transport Proteins/metabolism
3.
Eur J Pharmacol ; 671(1-3): 39-44, 2011 Dec 05.
Article in English | MEDLINE | ID: mdl-21963455

ABSTRACT

Major depression disorder is a significant health problem with 10-20% of all adults suffering from this disease. The underlying causes of depression are still unclear and 15% of depressed patients are resistant to all known therapies. Monoamine therapies have so far been the most successful approach for treating depression. Triple monoamine reuptake inhibitors have recently been implicated in generation of potent antidepressant activity while possibly exhibiting a low side-effect profile in addition to treating anhedonia. The additional, previously under-appreciated involvement of dopaminergic systems in depression prompted our efforts to develop novel asymmetric trisubstituted and disubstituted pyran derivatives as triple reuptake inhibitors. One of the lead compounds, D-142, exhibited uptake inhibition (K(i)) values of 29.3 nM, 14.7 nM and 59.3 ± 13.7 nM for norepinephrine, serotonin and dopamine transporters, respectively. Its affinity for serotonin transporter was comparable to fluoxetine, a well known SSRI. In the rat forced swimming test, compound D-142 exhibited potent antidepressant activity in the dose range tested (2.5, 5 and 10mg/kg) and was far more efficacious than the reference compound imipramine. In the mouse tail suspension test, compound D-142 reduced immobility in a dose (2.5, 5 and 10mg/kg) dependent manner, indicating a potent antidepressant effect. In locomotor activity tests, compound D-142 did not exhibit any stimulation in the same dose ranges. In the extended CNS receptors screening assay this molecule exhibited little or no non-specific interaction in the CNS, indicating high specificity for monoamine transporters. These results advance D-142 as a potential potent antidepressant.


Subject(s)
Antidepressive Agents/chemistry , Antidepressive Agents/pharmacology , Biogenic Monoamines/metabolism , Neurotransmitter Uptake Inhibitors/chemistry , Neurotransmitter Uptake Inhibitors/pharmacology , Pyrans/chemistry , Pyrans/pharmacology , Animals , Behavior, Animal/drug effects , Biological Transport/drug effects , Central Nervous System/drug effects , Central Nervous System/metabolism , Drug Discovery , Hindlimb Suspension , Male , Mice , Motor Activity/drug effects , Rats , Swimming , Symporters/antagonists & inhibitors
4.
Tetrahedron Asymmetry ; 22(10): 1081-1086, 2011 May 31.
Article in English | MEDLINE | ID: mdl-21927543

ABSTRACT

Triple monoamine reuptake inhibitors have been implicated in the development of a new generation of antidepressants with higher efficacy than the currently existing therapies. In this paper, we have developed an alternative efficient synthetic route for triple monoamine reuptake inhibitor D-142 in 18.5% overall yield in 11 steps starting from diphenylmethane. D-142 was developed by us recently. The key step of the present synthetic strategy is the preferential formation of a bromohydrin from olefin via a cis-bromoinum intermediate, which introduced significant efficiency in the overall synthesis. Furthermore, we have developed an efficient way to recycle the optically active intermediate diol back to the desired chiral epoxide.

5.
J Med Chem ; 54(8): 2924-32, 2011 Apr 28.
Article in English | MEDLINE | ID: mdl-21446715

ABSTRACT

To investigate structural alterations of the lead triple uptake inhibitor molecule, disubstituted 4-((((3S,6S)-6-benzhydryltetrahydro-2H-pyran-3-yl)amino)methyl)phenol, we have carried out structure-activity relationship (SAR) studies to investigate the effect of alteration of aromatic substitutions and introduction of heterocyclic aromatic moieties on this molecular template. The novel compounds were tested for their affinities for the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET) in the brain by measuring their potency in inhibiting the uptake of [(3)H]DA, [(3)H]5-HT, and [(3)H]NE, respectively. SAR results indicate dopamine norepinephrine reuptake inhibitory (DNRI) type activity in thiophene (10g) and pyrrole (10i) derivatives. On the other hand, 3-hydroxyphenyl derivative 10f and 4-methoxyphenyl derivative 10j exhibited a triple reuptake inhibitory (TUI) activity profile, as these molecules exhibited potent uptake inhibition for all the monoamine transporters (K(i) of 31.3, 40, 38.5 and K(i) of 15.9, 12.9, 29.3 for DAT, SERT, and NET for 10f and 10g, respectively). Compound 10f was further evaluated in the rat forced swim test to evaluate its potential antidepressant effect. The results show significant reduction of immobility by TUI 10f at 10 mg/kg dose, indicating potential antidepressant activity.


Subject(s)
Antidepressive Agents/chemistry , Antidepressive Agents/pharmacology , Neurotransmitter Uptake Inhibitors/chemistry , Neurotransmitter Uptake Inhibitors/pharmacology , Pyrans/chemistry , Pyrans/pharmacology , Animals , Antidepressive Agents/metabolism , Brain/metabolism , Magnetic Resonance Spectroscopy , Pyrans/metabolism , Rats , Structure-Activity Relationship
6.
Bioorg Med Chem ; 18(15): 5661-74, 2010 Aug 01.
Article in English | MEDLINE | ID: mdl-20605099

ABSTRACT

Here we report a structure-activity relationship (SAR) study of analogues of 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol. Our SAR is focused on introduction of various substitutions in the piperazine ring of the hybrid template. The goal behind this study is to delineate the nature of the binding pocket for N-aryl substitution in the piperazine ring by observing the effect of various hydrophobic and other heteroaromatic substitutions on binding affinity (K(i)), as measured with tritiated spiperone and HEK-293 cells expressing either D(2) or D(3) receptors. Functional activity of selected compounds was assessed with the GTPgammaS binding assay. Compound 8d was the most selective for the D(3) receptor in the spiperone binding assay. An interesting similarity in binding affinity was observed between isoquinoline derivative D-301 and the 2-substituted pyridine derivative 8d, suggesting the importance of relative spatial relationships between the N-atom of the ligand and the molecular determinants of the binding pocket in D(2)/D(3) receptors. Functional activity assays demonstrated high potency and selectivity of (+)-8a and (-)-28b (D(2)/D(3) (ratio of EC(50)): 105 and 202, respectively) for the D(3) receptor and both compounds were more selective compared to the reference drug ropinirole (D(2)/D(3) (ratio of EC(50)): 29.5).


Subject(s)
Biphenyl Compounds/chemistry , Piperazines/chemistry , Receptors, Dopamine D2/metabolism , Receptors, Dopamine D3/metabolism , Tetrahydronaphthalenes/chemistry , Binding Sites , Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/pharmacology , Cell Line , Humans , Hydrophobic and Hydrophilic Interactions , Piperazine , Piperazines/chemical synthesis , Piperazines/pharmacology , Stereoisomerism , Structure-Activity Relationship , Tetrahydronaphthalenes/chemical synthesis , Tetrahydronaphthalenes/pharmacology
7.
Bioorg Med Chem ; 17(18): 6699-706, 2009 Sep 15.
Article in English | MEDLINE | ID: mdl-19682914

ABSTRACT

S-ribosylhomocysteinase (LuxS) catalyzes the cleavage of the thioether bond of S-ribosylhomocysteine (SRH) to produce homocysteine and 4,5-dihydroxy-2,3-pentanedione (DPD), which is the precursor of type 2 autoinducer for bacterial cell-cell communication. In this work, we have synthesized several SRH analogues modified at the ribose C3 position as potential inhibitors of LuxS. While removal or methylation of the C3-OH resulted in simple competitive inhibitors of moderate potency, inversion of the C3 stereochemistry or substitution of fluorine for C3-OH resulted in slow-binding inhibitors of improved potency. The most potent inhibitor showed a K(I)(*) value of 0.43 microM.


Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Bacterial Proteins/metabolism , Carbon-Sulfur Lyases/antagonists & inhibitors , Carbon-Sulfur Lyases/metabolism , Homocysteine/analogs & derivatives , Bacillus subtilis/drug effects , Bacillus subtilis/metabolism , Homocysteine/chemistry , Homocysteine/pharmacology , Ribose/chemistry , Structure-Activity Relationship
8.
J Am Chem Soc ; 131(3): 1243-50, 2009 Jan 28.
Article in English | MEDLINE | ID: mdl-19099445

ABSTRACT

S-Ribosylhomocysteinase (LuxS) cleaves the thioether bond in S-ribosylhomocysteine (SRH) to produce homocysteine (Hcys) and 4,5-dihydroxy-2,3-pentanedione (DPD), the precursor of the type II bacterial quorum sensing molecule (AI-2). The catalytic mechanism of LuxS comprises three distinct reaction steps. The first step involves carbonyl migration from the C1 carbon of ribose to C2 and the formation of a 2-ketone intermediate. The second step shifts the C=O group from the C2 to C3 position to produce a 3-ketone intermediate. In the final step, the 3-ketone intermediate undergoes a beta-elimination reaction resulting in the cleavage of the thioether bond. In this work, the 3-ketone intermediate was chemically synthesized and shown to be chemically and kinetically competent in the LuxS catalytic pathway. Substrate analogues halogenated at the C3 position of ribose were synthesized and reacted as time-dependent inhibitors of LuxS. The time dependence was caused by enzyme-catalyzed elimination of halide ions. Examination of the kinetics of halide release and decay of the 3-ketone intermediate catalyzed by wild-type and mutant LuxS enzymes revealed that Cys-84 is the general base responsible for proton abstraction in the three reaction steps, whereas Glu-57 likely facilitates substrate binding and proton transfer during catalysis.


Subject(s)
Bacterial Proteins/analysis , Bacterial Proteins/metabolism , Biocatalysis , Carbon-Sulfur Lyases/analysis , Carbon-Sulfur Lyases/metabolism , Catalytic Domain , Homocysteine/chemistry , Homocysteine/metabolism , Ketones/chemistry , Ketones/metabolism , Kinetics , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Structure , Substrate Specificity , Time Factors
9.
Org Lett ; 10(20): 4605-8, 2008 Oct 16.
Article in English | MEDLINE | ID: mdl-18798640

ABSTRACT

Fully protected 3,5-difluorotyrosine (F2Y), Fmoc-F2Y(tBu)-OH, is efficiently prepared by a chemoenzymatic process and incorporated into individual peptides and combinatorial peptide libraries. The F2Y-containing peptides display kinetic properties toward protein tyrosine phosphatases (PTPs) similar to their corresponding tyrosine-containing counterparts but are resistant to tyrosinase action. These properties make F2Y a useful tyrosine surrogate during peptide library screening for optimal PTP substrates.


Subject(s)
Peptides/chemical synthesis , Peptides/metabolism , Protein Tyrosine Phosphatases/metabolism , Tyrosine/analogs & derivatives , Chromatography, High Pressure Liquid , Kinetics , Molecular Structure , Peptides/chemistry , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Substrate Specificity , Tyrosine/chemistry
10.
J Am Chem Soc ; 128(39): 13000-9, 2006 Oct 04.
Article in English | MEDLINE | ID: mdl-17002397

ABSTRACT

Cyclic peptides provide attractive lead compounds for drug discovery and excellent molecular probes in biomedical research. Large combinatorial libraries of cyclic peptides can now be routinely synthesized by the split-and-pool method and screened against biological targets. However, post-screening sequence determination of hit peptides has been problematic. In this report, a high-throughput method for the sequence determination of cyclic peptide library members has been developed. TentaGel microbeads (90 mum) were spatially segregated into outer and inner layers; cyclic peptides were displayed on the bead surface, whereas the inner core of each bead contained the corresponding linear peptide as the encoding sequence. After screening of the cyclic peptide library against a macromolecular target, the identity of hit peptides was determined by sequencing the linear encoding peptides inside the bead using a partial Edman degradation/mass spectrometry method. On-bead screening of an octapeptide library (theoretical diversity of 160 000) identified cyclic peptides that bind to streptavidin. A 400-member library of tyrocidine A analogues was synthesized on TentaGel macrobeads and solution-phase screening of the library directly against bacterial cells identified a tyrocidine analogue of improved antibacterial activity. Our results demonstrate that the new method for cyclic peptide sequence determination is reliable, operationally simple, rapid, and inexpensive and should greatly expand the utility of cyclic peptides in biomedical research.


Subject(s)
Peptides, Cyclic/analysis , Sequence Analysis, Protein/methods , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Combinatorial Chemistry Techniques/methods , Oligopeptides/analysis , Oligopeptides/chemistry , Peptide Library , Peptides, Cyclic/chemistry , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods , Streptavidin/chemistry , Tyrocidine/chemical synthesis , Tyrocidine/chemistry , Tyrocidine/pharmacology
SELECTION OF CITATIONS
SEARCH DETAIL
...