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1.
Bioorg Med Chem Lett ; 82: 129151, 2023 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-36690040

RESUMO

A novel series of 1,3,5­trioxazatriquinane with multiple effective residues (TriMER) derivatives with amino-methylene side chains was designed and synthesized based on the docking-simulation results between orexin receptors (OXRs) and TriMER-type OXR antagonists. In vitro screening against orexin receptors identified six TriMER derivatives with a cis side-chain configuration, and, among these, 20d and 28d showed full agonist activity against OX2R at a concentration of 10 µM. To determine the absolute stereochemistry of these hit compounds, we also conducted the first asymmetric synthesis of a 1,3,5­trioxazatriquinane skeleton using a Katsuki-Sharpless asymmetric epoxidation as the key reaction and obtained a set of the individual stereoisomers. After evaluating their activity, (+)-20d (EC50 = 3.87 µM for OX2R) and (+)-28d (EC50 = 1.62 µM for OX2R) were determined as eutomers for OX2R agonist activity. Our results provide a new class of skeleton consisting of an (R)-1,3,5­trioxazatriquinane core with flexible methylene linkers and hydrophobic substituents at the terminals of the side chains via carbamates/sulfonamides as OX2R agonists.


Assuntos
Antagonistas dos Receptores de Orexina , Esqueleto , Receptores de Orexina/agonistas , Orexinas , Antagonistas dos Receptores de Orexina/farmacologia
2.
Bioorg Med Chem Lett ; 59: 128527, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35007722

RESUMO

To investigate the contribution of hydrogen bonding between the 14-hydroxy group and the 6-amide chain on the binding affinity of nalfurafine toward KOR and OX1R, we prepared the 14-H and 14-dehydrated nalfurafine and their five-membered D-ring nalfurafine (D-nor-nalfurafine) derivatives. The 14-H and 14-dehydrated nalfurafine derivatives showed almost the same affinity for KOR as nalfurafine and more potent affinity for OX1R. On the other hand, 14-H and 14-dehydrated D-nor-nalfurafine derivatives showed weak affinity for KOR and almost no affinity for OX1R. The conformational analyses suggested that the 6-amide chains of the nalfurafine derivatives are mainly oriented just at or downward from the C-ring, while those of the D-nor-nalfurafine derivatives were mainly oriented toward the upper side of the C-ring even in the absence of the 14-hydroxy group. We postulated that the ion-dipole interaction between the 6-amide and the 16-nitrogen might stabilize the upwardly oriented 6-amide group. These results suggested that the 14-hydroxy group and the ion-dipole interaction would play important roles in the orientation of the 6-amide group, which might control the affinity between KOR and OX1R.


Assuntos
Morfinanos/farmacologia , Receptores de Orexina/metabolismo , Receptores Opioides/metabolismo , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Estrutura Molecular , Morfinanos/síntese química , Morfinanos/química , Relação Estrutura-Atividade
3.
Bioorg Med Chem Lett ; 59: 128530, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35007725

RESUMO

A novel series of naphthalene derivatives were designed and synthesized based on the strategy focusing on the restriction of the flexible bond rotation of OX2R selective agonist YNT-185 (1) and their agonist activities against orexin receptors were evaluated. The 1,7-naphthalene derivatives showed superior agonist activity than 2,7-naphthalene derivatives, suggesting that the bent form of 1 would be favorable for the agonist activity. The conformational analysis of 1,7-naphthalene derivatives indicated that the twisting of the amide unit out from the naphthalene plane is important for the enhancement of activity. The introduction of a methyl group on the 2-position of 1,7-naphthalene ring effectively increased the activity, which led to the discovery of the potent OX2R agonist 28c (EC50 = 9.21 nM for OX2R, 148 nM for OX1R). The structure-activity relationship results were well supported by a comparison of the docking simulation results of the most potent derivative 28c with an active state of agonist-bound OX2R cryo-EM SPA structure. These results suggested important information for understanding the active conformation and orientation of pharmacophores in the orexin receptor agonists, which is expected as a chemotherapeutic agent for the treatment of narcolepsy.


Assuntos
Compostos de Anilina/farmacologia , Benzamidas/farmacologia , Desenho de Fármacos , Naftalenos/farmacologia , Receptores de Orexina/agonistas , Compostos de Anilina/síntese química , Compostos de Anilina/química , Benzamidas/síntese química , Benzamidas/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Naftalenos/síntese química , Naftalenos/química , Relação Estrutura-Atividade
4.
Bioorg Med Chem Lett ; 56: 128485, 2022 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-34861349

RESUMO

Mas-related G protein-coupled receptor X2 (MRGPRX2) mediates the itch response in neurons and is involved in atopic dermatitis (AD)-associated inflammation and itch. Potent and MRGPRX2-selective ligands are essential to an understanding of the detailed function of the receptor and to develop new therapeutic agents for its related diseases. (+)-TAN-67 (1), the enantiomer of the δ-opioid receptor (DOR) selective ligand (-)-TAN-67 (1), has been reported to activate MRGPRX2, although (+)-1 also interacts with DOR, which prevents investigators from interrogating the function of MRGPRX2. Here, we have succeeded in developing a novel unnatural morphinan compound (+)-2a by a transformation based on the structure of (+)-1, which removes the DOR binding affinity. (+)-2a activated both human MRGPRX2 and the mouse orthologue Mrgprb2 in in vitro experiments and induced itch-like behaviors in mice to the same extent as (+)-1. The (+)-2a-induced itch response in mice was suppressed by administration of the tripeptide QWF, an MRGPRX2/Mrgprb2 antagonist, or the antipruritic drug nalfurafine. Together, (+)-2a serves as a useful tool to elucidate the itch-related function/action of MRGPRX2 and its mouse orthologue Mrgprb2.


Assuntos
Comportamento Animal/efeitos dos fármacos , Desenvolvimento de Medicamentos , Morfinanos/efeitos adversos , Proteínas do Tecido Nervoso/metabolismo , Prurido/induzido quimicamente , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/metabolismo , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Ligantes , Camundongos , Estrutura Molecular , Morfinanos/síntese química , Morfinanos/química , Proteínas do Tecido Nervoso/antagonistas & inibidores , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Receptores Opioides delta , Relação Estrutura-Atividade
5.
Bioorg Med Chem Lett ; 59: 128550, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35041942

RESUMO

The five-membered D-ring nalfurafine (d-nor-nalfurafine) derivatives with a 16-sulfonamide group were synthesized. Conversion of the 16-cyclopropylmethyl group to the 16-benzenesulfonamide group in the d-nor-nalfurafine derivatives drastically improved the orexin 1 receptor (OX1R) antagonist activities. The intramolecular hydrogen bond between the 14-hydroxy and the 16-sulfonamide groups may play an important role in increasing the probability that the 6-amide group would be located at the lower side of the C-ring, leading to an active conformation for OX1R. The assay results and the conformational analyses of the 14-OH, 14-H, and 14-dehydrated d-nor-nalfurafine derivatives suggested that the 14- and 16-substituents of the d-nor-nalfurafine derivatives had a greater effect on the affinities for the OX1R than did the 14- and 17-substituents of nalfurafine derivatives.


Assuntos
Morfinanos/farmacologia , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/metabolismo , Compostos de Espiro/farmacologia , Sulfonamidas/farmacologia , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Morfinanos/química , Antagonistas dos Receptores de Orexina/química , Compostos de Espiro/química , Relação Estrutura-Atividade , Sulfonamidas/química
6.
Bioorg Med Chem Lett ; 60: 128555, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35051577

RESUMO

A novel series of 1-amino-tetralin derivatives were designed and synthesized based on the putative binding mode of the naphthalene-type orexin receptor agonist 5 and their agonist activities against orexin receptors were evaluated. The introduction of N-methyl-(3-methoxyphenyl)acetamide unit onto the 1-amino-tetralin skeleton remarkably enhanced the potency of the agonist. The asymmetric synthesis of 6 revealed that (-)-6 having a (S)-1-amino-tetralin skeleton showed a OX2R selective agonist activity (EC50 = 2.69 nM for OX2R, OX1R/OX2R = 461) yet its enantiomer (R)-(+)-6 showed a potent OX1/2R dual agonist activity (EC50 = 13.5 nM for OX1R, 0.579 nM for OX2R, OX1R/OX2R = 23.3). These results suggested that upward orientation of the amide side chain against the tetralin scaffold (S-configuration) would be selective for OX2R activation, and the downward orientation (R-configuration) would be significant for dual agonist activity. To our best knowledge, there have been no reports thus far that the stereochemistry of one carbon center on the agonist structure regulates the orexin receptor selectivity. Our results would provide important information for the development of OX1R selective agonists.


Assuntos
Descoberta de Drogas , Receptores de Orexina/agonistas , Tetra-Hidronaftalenos/farmacologia , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Tetra-Hidronaftalenos/síntese química , Tetra-Hidronaftalenos/química
7.
Bioorg Med Chem Lett ; 30(3): 126893, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31879208

RESUMO

The morphinan-type orexin 1 receptor (OX1R) antagonists such as YNT-707 (2) and YNT-1310 (3) show potent and extremely high selective antagonistic activity against OX1R. In the course of our studies of the essential structure of 2, we identified new scaffolds by simplification of the morphinan skeleton. However, the new chemical entities carrying the D-ring removed scaffold showed insufficient activity. To improve the activity of these derivatives, we investigated the effect of substituents mainly focused on the 17-nitrogen group. The 17-N-substituted derivatives, as well as the cyclic derivatives, were synthesized and examined the OX1R antagonistic activity. The assay results showed the interesting relationship between the OX1R antagonistic activity and the substituents on the 17-nitrogen: the antagonistic activity was increased as the bulkiness of 17-substituents increased. Finally, the 17-N-Boc derivative 14a showed the most potent OX1R antagonistic activity (Ki = 14.8 nM).


Assuntos
Morfinanos/química , Antagonistas dos Receptores de Orexina/química , Receptores de Orexina/química , Sulfonamidas/química , Aminas/química , Humanos , Cinética , Morfinanos/metabolismo , Antagonistas dos Receptores de Orexina/síntese química , Antagonistas dos Receptores de Orexina/metabolismo , Receptores de Orexina/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/metabolismo
8.
Bioorg Med Chem Lett ; 30(17): 127360, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32738987

RESUMO

The D-nor-nalfurafine derivatives, which were synthesized by contraction of the six-membered D-ring in nalfurafine (1), had no affinity for orexin 1 receptors (OX1Rs). The 17N-lone electron pair in 1 oriented toward the axial direction, while that of D-nor-derivatives was directed in the equatorial configuration. The axial lone electron pair can form a hydrogen bond with the 14-hydroxy group, which could push the 6-amide side chain toward the downward direction with respect to the C-ring. The resulting conformation would be an active conformation for binding with OX1R. The dual affinities of 1 for OX1R and κ opioid receptor (KOR) led us to elucidate the mechanism by which only 1 showed no aversion but U-50488H. Actually, 1 selectively induced severe aversion in OX1R knockout mice, but not in wild-type mice. These results well support that OX1R suppresses the aversion of 1. This is the elucidation of long period puzzle which 1 showed no aversion in KOR.


Assuntos
Morfinanos/química , Antagonistas dos Receptores de Orexina/síntese química , Receptores de Orexina/metabolismo , Compostos de Espiro/química , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Sítios de Ligação , Camundongos , Camundongos Knockout , Conformação Molecular , Simulação de Acoplamento Molecular , Morfinanos/metabolismo , Morfinanos/farmacologia , Antagonistas dos Receptores de Orexina/metabolismo , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/química , Receptores de Orexina/genética , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/metabolismo , Compostos de Espiro/metabolismo , Compostos de Espiro/farmacologia
9.
Molecules ; 25(5)2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-32131542

RESUMO

7-Benzylidenenaltrexone (BNTX) and most of its derivatives showed in vitro antimalarial activities against chloroquine-resistant and -sensitive Plasmodium falciparum strains (K1 and FCR3, respectively). In addition, the time-dependent changes of the addition reactions of the BNTX derivatives with 1-propanethiol were examined by 1H-NMR experiments to estimate their thiol group-trapping ability. The relative chemical reactivity of the BNTX derivatives to trap the thiol group of 1-propanethiol was correlated highly with the antimalarial activity. Therefore, the measurements of the thiol group-trapping ability of the BNTX derivatives with a Michael acceptor is expected to become an alternative method for in vitro malarial activity and related assays.


Assuntos
Compostos de Benzilideno , Morfinanos , Naltrexona/análogos & derivados , Plasmodium falciparum/crescimento & desenvolvimento , Antimaláricos/síntese química , Antimaláricos/química , Antimaláricos/farmacologia , Compostos de Benzilideno/química , Compostos de Benzilideno/farmacologia , Humanos , Morfinanos/química , Morfinanos/farmacologia , Naltrexona/química , Naltrexona/farmacologia , Ressonância Magnética Nuclear Biomolecular , Relação Estrutura-Atividade
10.
Bioorg Med Chem Lett ; 29(18): 2655-2658, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31375290

RESUMO

The orexin 1 receptor (OX1R) antagonists carrying a morphinan skeleton such as YNT-707 (2) and YNT-1310 (3) showed potent and extremely high selective antagonistic activity against OX1R. In the course of our study of the essential structure of YNT-707 for high binding affinity against OX1R, we prepared derivatives of 2 without the D- and 4,5-epoxy rings to clarify the roles of these structural determinants toward OX1R antagonistic activity. The D- and 4,5-epoxy rings played important roles for the active orientation of the 17-sulfonamide and 6-amide side chains. Finally, we identified the simple structure required for selective OX1R antagonistic activity in the complex morphinan skeleton, which is expected to be a useful scaffold for further design of OX1R ligands.


Assuntos
Morfinanos/farmacologia , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/metabolismo , Sulfonamidas/farmacologia , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Morfinanos/síntese química , Morfinanos/química , Antagonistas dos Receptores de Orexina/síntese química , Antagonistas dos Receptores de Orexina/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
11.
Bioorg Med Chem ; 27(8): 1747-1758, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30871861

RESUMO

Morphinan derivatives lacking the 4,5-epoxy ring were synthesized to examine the participation of the 14-OH group, the 3-OMe group, and the aromaticity of the A-ring in the activity and selectivity for the orexin 1 receptor (OX1R). The assay results and the conformational analyses of the 14-dehydrated and 14-H derivatives suggested that the orientations of the 6-amide side chain and the 17-benzenesulfonyl group would play important roles in the activity for OX1R. In the 6ß-derivatives, removal of the 3-OMe group and the reduction of the A-ring significantly decreased the activity toward the OX1R, but these changes did not affect the 6α-derivatives. These results indicate that the 3-OMe group and the A-ring would be essential structural moieties for the 6ß-derivatives.


Assuntos
Morfinanos/química , Morfinanos/farmacologia , Antagonistas dos Receptores de Orexina/química , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacologia , Desenho de Fármacos , Humanos , Modelos Moleculares , Conformação Molecular , Receptores de Orexina/química
12.
Bioorg Med Chem Lett ; 28(4): 774-777, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29338909

RESUMO

The 14-dehydration- and 14-H derivatives of the orexin 1 receptor (OX1R) antagonist YNT-707 (2) were synthesized. The obtained derivatives showed higher affinities for OX1R than the corresponding 14-hydroxy derivatives. The conformational analysis suggested that the 17-sulfonamide groups in the derivatives without the 14-hydroxy group have a greater tendency to be oriented toward the upper side of the D-ring compared with the 14-hydroxy derivatives. Additionally, the 14-dehydration-derivative with 6α-amide side chain showed significantly higher affinity than the 14-hydroxy derivative, while the corresponding 14-H derivative showed only slightly higher affinity. Thus, the 14-hydroxy group strongly affects the affinity of the antagonist for the OX1R.


Assuntos
Morfinanos/química , Antagonistas dos Receptores de Orexina/química , Sulfonamidas/química , Conformação Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Morfinanos/síntese química , Antagonistas dos Receptores de Orexina/síntese química , Estereoisomerismo , Sulfonamidas/síntese química
13.
Bioorg Med Chem Lett ; 27(17): 4176-4179, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28739044

RESUMO

The essential structure of the orexin 1 receptor (OX1R) antagonist YNT-707 (2) was clarified, particularly the roles to OX1R antagonist activities of the 3-OMe, the 4,5-epoxy ring, the 14-hydroxy group, and the orientation of the 6-amide side chain. The 3-OMe and 17-sulfonamide group were shown to be essential for the OX1R antagonistic activity. The 4,5-epoxy ring plays an important role for the active orientation of the 6-amide group. The 14-hydroxy group could lower the activity of the 6ß-amide isomer by the interaction of the 14-hydroxy group with the 6-amide group, which could orient the 6-amide group toward the upper side of the C-ring. Finally, we proposed the difference in the active conformation between OX1R and κ opioid receptor (KOR), especially in the orientation of the 6-amide group which is expected to be a useful guide for medicinal chemists to design OX1R ligands.


Assuntos
Compostos de Epóxi/farmacologia , Morfinanos/farmacologia , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/metabolismo , Sulfonamidas/farmacologia , Sítios de Ligação/efeitos dos fármacos , Relação Dose-Resposta a Droga , Compostos de Epóxi/química , Humanos , Estrutura Molecular , Morfinanos/síntese química , Morfinanos/química , Antagonistas dos Receptores de Orexina/síntese química , Antagonistas dos Receptores de Orexina/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
14.
Bioorg Med Chem ; 25(16): 4375-4383, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28662966

RESUMO

The 7-benzylidenenaltrexone (BNTX) derivatives 2a-v, 3a-c, 13a-c, and 14a were synthesized from naltrexone (1) and evaluated for their antitrichomonal activity. The structure-activity-relationship studies found that 4-iodo-BNTX (2g) showed the highest activity (IC50=10.5µM) and the affinity for the opioid receptor was less important for antitrichomonal activity against Trichomonas vaginalis. The morphinan skeleton bearing both the double bond for a Michael acceptor and the phenolic hydroxy group would be a specific template for development of antitrichomonal agents. In addition, the mechanism of the antitrichomonal activity of the BNTX derivatives may differ from that of the standard drug, metronidazole.


Assuntos
Antitricômonas/farmacologia , Compostos de Benzilideno/farmacologia , Naltrexona/análogos & derivados , Receptores Opioides delta/antagonistas & inibidores , Trichomonas vaginalis/efeitos dos fármacos , Animais , Antitricômonas/síntese química , Antitricômonas/química , Compostos de Benzilideno/síntese química , Compostos de Benzilideno/química , Células CHO , Cricetulus , Relação Dose-Resposta a Droga , Estrutura Molecular , Naltrexona/síntese química , Naltrexona/química , Naltrexona/farmacologia , Relação Estrutura-Atividade
15.
Chem Pharm Bull (Tokyo) ; 64(9): 1364-9, 2016 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-27321228

RESUMO

The ZnCl2-promoted intramolecular hetero-Diels-Alder reaction of N-(ortho-propargylphenyl)-N'-arylcarbodiimides, in which the aryl-N=C moiety functioned as a 2-azabuta-1,3-diene, 4π component, has been achieved. By this method, very rare 5,12-dihydrodibenzo[b,g][1,8]naphthyridines and fully aromatized dibenzo[b,g][1,8]naphthyridines were successfully synthesized.


Assuntos
Alcinos/química , Cloretos/química , Imidas/química , Naftiridinas/síntese química , Compostos de Zinco/química , Reação de Cicloadição , Estrutura Molecular , Naftiridinas/química
16.
Bioorg Med Chem Lett ; 25(21): 4890-4892, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-26099536

RESUMO

We evaluated antitrichomonal effects of δ opioid receptor (DOR) agonists and antagonists. Although all the agonists were inactive, the DOR antagonists BNTX (2a) and its derivatives 2b-d showed antitrichomonal activity with MIC of 20-40 µM. In addition, the development of a more effective synthetic method for the BNTX derivatives was achieved by using the Knoevenagel condensation.


Assuntos
Antitricômonas/química , Antitricômonas/farmacologia , Compostos de Benzilideno/farmacologia , Naltrexona/análogos & derivados , Receptores Opioides delta/agonistas , Receptores Opioides delta/antagonistas & inibidores , Vaginite por Trichomonas/tratamento farmacológico , Antitricômonas/síntese química , Compostos de Benzilideno/síntese química , Compostos de Benzilideno/química , Relação Dose-Resposta a Droga , Feminino , Humanos , Estrutura Molecular , Naltrexona/síntese química , Naltrexona/química , Naltrexona/farmacologia , Relação Estrutura-Atividade
17.
Bioorg Med Chem ; 23(19): 6271-9, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26346669

RESUMO

We designed and synthesized pentacyclic propellane derivatives with a 6-amide side chain to afford compounds with higher MOR/KOR ratio and lower sedative effects than nalfurafine. The obtained etheno-bridged derivative with a ß-amide side chain, YNT-854, showed a higher MOR/KOR ratio than nalfurafine. YNT-854 also exhibited a higher dose ratio between the sedative effect and the analgesic effect than observed with nalfurafine, which may guide the future design of useful analgesics with a weaker sedative effect than nalfurafine.


Assuntos
Amidas/química , Analgésicos Opioides/síntese química , Morfinanos/síntese química , Compostos de Espiro/síntese química , Analgésicos Opioides/metabolismo , Analgésicos Opioides/uso terapêutico , Animais , Células CHO , Cricetinae , Cricetulus , Cobaias , Masculino , Camundongos , Camundongos Endogâmicos ICR , Morfinanos/química , Morfinanos/metabolismo , Morfinanos/uso terapêutico , Dor/induzido quimicamente , Dor/tratamento farmacológico , Ligação Proteica , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/agonistas , Receptores Opioides mu/metabolismo , Compostos de Espiro/química , Compostos de Espiro/metabolismo , Compostos de Espiro/uso terapêutico , Relação Estrutura-Atividade
18.
Bioorg Med Chem Lett ; 24(13): 2851-4, 2014 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-24835200

RESUMO

Indolopropellane 2 was reported to show almost no binding affinity to the δ opioid receptor (DOR) in spite of the fact that 2 has both the propellane fundamental skeleton (message part) with binding ability to the opioid receptors and a possible DOR address structure (indole moiety). We developed the working hypothesis that almost no binding affinity of 2 to the DOR would be derived from its possibly stable bent conformer. To enable the propellane skeleton to adopt an extended conformation which would reasonably interact with the DOR, quinolinopropellanes 3a-d were designed which had an additional pharmacophore, quinoline nitrogen. The calculated binding free energies of ligand-DOR complexes strongly supported our working hypothesis. The synthesized quinolinopropellane 3a was a selective DOR full agonist, confirming our working hypothesis and the results of in silico investigation.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/farmacologia , Desenho de Fármacos , Quinolinas/farmacologia , Receptores Opioides delta/agonistas , Hidrocarbonetos Aromáticos com Pontes/síntese química , Hidrocarbonetos Aromáticos com Pontes/química , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Conformação Molecular , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade
19.
Bioorg Med Chem Lett ; 23(1): 268-72, 2013 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-23200250

RESUMO

We have previously reported the essential structure of the opioid κ receptor agonist nalfurafine hydrochloride (TRK-820) for binding to the κ receptor. In the course of this study, we focused on the effect of the substituent at 17-N in nalfurafine on the binding affinity for the κ receptor. The exchange of the 17-N substituent in nalfurafine from cyclopropylmethyl to fluoro-substituted alkyl groups, which are strong electron withdrawing substituents, almost completely diminished the binding affinities for the µ and δ opioid receptors, but the binding affinity for the κ receptor was still maintained. As a result, nalfurafine derivatives with 17-fluoro-substituted alkyl groups showed higher selectivities for the κ receptor than did nalfurafine itself. With regard to the κ agonistic activities, the conversion of the 17-N substituent in nalfurafine from cyclopropylmethyl to fluoro-substituted alkyl groups led to the gradual decrease of the agonistic activities in the order corresponding to their binding affinities for the κ receptor. In contrast, the derivative with the bulky 17-isobutyl group showed lower affinity and agonistic activity for the κ receptor than the derivatives with the smaller functional groups. This research suggested that both the electronic property and the steric characteristics of the 17-N substituent would have a great influence on the binding property for the κ receptor.


Assuntos
Morfinanos/química , Receptores Opioides kappa/metabolismo , Compostos de Espiro/química , Dinorfinas/química , Morfinanos/síntese química , Morfinanos/metabolismo , Nitrogênio/química , Ligação Proteica , Receptores Opioides delta/química , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/química , Receptores Opioides mu/química , Receptores Opioides mu/metabolismo , Compostos de Espiro/síntese química , Compostos de Espiro/metabolismo
20.
Org Lett ; 25(19): 3407-3411, 2023 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-37154730

RESUMO

The reaction of 14-aminonaltrexone with acetic anhydride was found to produce a range of different novel compounds between the free compound and its hydrochloride. The hydrochloride produced a compound with an acetylacetone moiety, whereas the free form produced a compound with a pyranopyridine moiety. Efforts to isolate reaction intermediates and density functional theory calculations have elucidated those formation mechanisms with both bearing the novel morphinan-type skeleton. Furthermore, a derivative with the acetylacetone moiety showed binding to opioid receptors.


Assuntos
Morfinanos , Pentanonas , Morfinanos/química , Esqueleto
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