RESUMEN
The morphinan skeleton is valued in drug discovery for its beneficial physicochemical properties and is recognized as a crucial template for opioid receptor ligands. In morphinan derivatives, it is well-established that the nitrogen atom within the piperidine ring (D-ring) interacts with the amino acid residues of the opioid receptors. This interaction is recognized as one of the crucial pharmacophores between the morphinan molecule and the opioid receptors. Consequently, the structure-activity relationships (SAR) surrounding the D-ring are not well-studied, due to concerns that structural transformations around the nitrogen at the 17-position could disrupt this interaction. In this study, we found that our novel morphinan-type ligands with a side chain containing a heteroatom positioned above the d-ring have binding affinity for the opioid receptors. These novel skeletons could provide unique templates with the desired side chain above the D-ring in the morphinan skeleton, and thus, potentially advance the SAR studies of morphinan ligands with the opioid receptors.
Asunto(s)
Morfinanos , Receptores Opioides , Receptores Opioides/metabolismo , Morfinanos/química , Receptores Opioides mu/metabolismo , Ligandos , Relación Estructura-Actividad , NitrógenoRESUMEN
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.
Asunto(s)
Morfinanos , Pentanonas , Morfinanos/química , EsqueletoRESUMEN
Orexins are a family of neuropeptides that regulate various physiological events, such as sleep/wakefulness as well as emotional and feeding behavior, and that act on two G-protein-coupled receptors, i.e., orexin 1 (OX1R) and orexin 2 receptors (OX2R). Since the discovery that dysfunction of the orexin/OX2R system causes the sleep disorder narcolepsy, several OX2R-selective and OX1/2R dual agonists have been disclosed. However, an OX1R-selective agonist has not yet been reported, despite the importance of the biological function of OX1R. Herein, we report the discovery of a potent OX1R-selective agonist, (R,E)-3-(4-methoxy-3-(N-(8-(2-(3-methoxyphenyl)-N-methylacetamido)-5,6,7,8-tetrahydronaphthalen-2-yl)sulfamoyl)phenyl)-N-(pyridin-4-yl)acrylamide [(R)-YNT-3708; EC50 = 7.48 nM for OX1R; OX2R/OX1R EC50 ratio = 22.5]. The OX1R-selective agonist (R)-YNT-3708 exhibited antinociceptive and reinforcing effects through the activation of OX1R in mice.
Asunto(s)
Neuropéptidos , Receptores Acoplados a Proteínas G , Ratones , Animales , Orexinas , Receptores de Orexina/agonistas , SueñoRESUMEN
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.
Asunto(s)
Antagonistas de los Receptores de Orexina , Esqueleto , Receptores de Orexina/agonistas , Orexinas , Antagonistas de los Receptores de Orexina/farmacologíaRESUMEN
Structurally diverse small compounds are utilized to obtain hit compounds that have suitable pharmacophores in appropriate three-dimensional conformations for the target drug receptors. We have focused on the 1,3,5-trioxazatriquinane skeleton, which has a rigid bowl-like structure enabling the diverse orientation of side chain units, leading to a novel small-scale focused library based on the skeleton. In the library screening for the orexin receptor, some of the compounds showed orexin receptor antagonistic activity with a high hit rate of 7%. By optimizing the hit compounds, we discovered a potent dual orexin receptor antagonist, 38b, and a selective orexin 1 receptor antagonist, 41b carrying the same plane structure. Both compounds showed reasonable brain permeability and beneficial effects when administered intraperitoneally to wild-type mice. Docking simulations of their eutomers, (-)-38b and (+)-41b, with orexin receptors suggested that the interaction between the 1,3,5-trioxazatriquinane core structure and the hydrophobic subpocket in orexin receptors enables a U-shape structure, which causes tight van der Waals interactions with the receptors similar to SB-334867, a selective orexin 1 receptor antagonist. These results indicate that the library approach utilizing the 1,3,5-trioxazatriquinanes bearing multiple effective residues (TriMERs) might be useful for the hit discovery process targeting not only opioid and orexin receptors but other G-protein coupled receptors.
Asunto(s)
Antagonistas de los Receptores de Orexina , Animales , Compuestos Heterocíclicos de 4 o más Anillos , Ratones , Antagonistas de los Receptores de Orexina/química , Antagonistas de los Receptores de Orexina/farmacología , Receptores de Orexina , Orexinas , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Descubrimiento de Drogas , Receptores de Orexina/agonistas , Tetrahidronaftalenos/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Relación Estructura-Actividad , Tetrahidronaftalenos/síntesis química , Tetrahidronaftalenos/químicaRESUMEN
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.
Asunto(s)
Morfinanos/farmacología , Receptores de Orexina/metabolismo , Receptores Opioides/metabolismo , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Estructura Molecular , Morfinanos/síntesis química , Morfinanos/química , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Compuestos de Anilina/farmacología , Benzamidas/farmacología , Diseño de Fármacos , Naftalenos/farmacología , Receptores de Orexina/agonistas , Compuestos de Anilina/síntesis química , Compuestos de Anilina/química , Benzamidas/síntesis química , Benzamidas/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Naftalenos/síntesis química , Naftalenos/química , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Morfinanos/farmacología , Antagonistas de los Receptores de Orexina/farmacología , Receptores de Orexina/metabolismo , Compuestos de Espiro/farmacología , Sulfonamidas/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Morfinanos/química , Antagonistas de los Receptores de Orexina/química , Compuestos de Espiro/química , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
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.
Asunto(s)
Conducta Animal/efectos de los fármacos , Desarrollo de Medicamentos , Morfinanos/efectos adversos , Proteínas del Tejido Nervioso/metabolismo , Prurito/inducido químicamente , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropéptido/metabolismo , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Humanos , Ligandos , Ratones , Estructura Molecular , Morfinanos/síntesis química , Morfinanos/química , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores de Neuropéptido/antagonistas & inhibidores , Receptores Opioides delta , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Morfinanos/química , Antagonistas de los Receptores de Orexina/síntesis química , Receptores de Orexina/metabolismo , Compuestos de Espiro/química , Animales , Reacción de Prevención/efectos de los fármacos , Sitios de Unión , Ratones , Ratones Noqueados , Conformación Molecular , Simulación del Acoplamiento Molecular , Morfinanos/metabolismo , Morfinanos/farmacología , Antagonistas de los Receptores de Orexina/metabolismo , Antagonistas de los Receptores de Orexina/farmacología , Receptores de Orexina/química , Receptores de Orexina/genética , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/metabolismo , Compuestos de Espiro/metabolismo , Compuestos de Espiro/farmacologíaRESUMEN
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.
Asunto(s)
Compuestos de Bencilideno , Morfinanos , Naltrexona/análogos & derivados , Plasmodium falciparum/crecimiento & desarrollo , Antimaláricos/síntesis química , Antimaláricos/química , Antimaláricos/farmacología , Compuestos de Bencilideno/química , Compuestos de Bencilideno/farmacología , Humanos , Morfinanos/química , Morfinanos/farmacología , Naltrexona/química , Naltrexona/farmacología , Resonancia Magnética Nuclear Biomolecular , Relación Estructura-ActividadRESUMEN
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).
Asunto(s)
Morfinanos/química , Antagonistas de los Receptores de Orexina/química , Receptores de Orexina/química , Sulfonamidas/química , Aminas/química , Humanos , Cinética , Morfinanos/metabolismo , Antagonistas de los Receptores de Orexina/síntesis química , Antagonistas de los Receptores de Orexina/metabolismo , Receptores de Orexina/metabolismo , Relación Estructura-Actividad , Sulfonamidas/metabolismoRESUMEN
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.
Asunto(s)
Morfinanos/farmacología , Antagonistas de los Receptores de Orexina/farmacología , Receptores de Orexina/metabolismo , Sulfonamidas/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Morfinanos/síntesis química , Morfinanos/química , Antagonistas de los Receptores de Orexina/síntesis química , Antagonistas de los Receptores de Orexina/química , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/químicaRESUMEN
In this study, the total synthesis of 3-epi-juruenolide C is achieved in 10 steps (longest linear sequence) starting from ethyl (2E,4S,5S)-4,5-dihydroxy-2-hexenoate. The synthetic highlights of our approach include one-pot regioselective bromination, intramolecular carbonylation using bis(triphenylphosphine)dicarbonylnickel, and face-selective hydrogenation using a homogeneous Wilkinson's catalyst.
Asunto(s)
Dioxoles/síntesis química , Lactonas/síntesis química , Catálisis , Complejos de Coordinación/química , Dioxoles/química , Halogenación , Hidrogenación , Lactonas/química , Níquel/química , Compuestos Organofosforados/química , EstereoisomerismoRESUMEN
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.
Asunto(s)
Morfinanos/química , Morfinanos/farmacología , Antagonistas de los Receptores de Orexina/química , Antagonistas de los Receptores de Orexina/farmacología , Receptores de Orexina/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacología , Diseño de Fármacos , Humanos , Modelos Moleculares , Conformación Molecular , Receptores de Orexina/químicaRESUMEN
The first total syntheses of 3- epi-litsenolide D2 and its enantiomer lincomolide A were achieved. The synthetic highlights of our approach include olefin cross metathesis and bromine addition to the generated double bond, followed by the regioselective HBr-elimination and intramolecular carbonylation using bis(triphenylphosphine)dicarbonylnickel. This investigation also revealed that the previously reported specific optical rotation of 3- epi-litsenolide D2 should be revised.
RESUMEN
The aldol condensation of naltrexone with various aryl aldehydes gives the corresponding 7-benzylidenenaltrexone derivatives in high yields. However, novel C-ring-contracted morphinan compounds were produced when 2-pyridinecarboxaldehyde or its related analogues were used as a coupling partner. The key structural feature was the existence of the tetrahydrofuran ring (4,5-epoxy ring, E-ring) of the morphinan skeleton. The time-resolved in situ IR spectroscopy of the reaction system indicated the short-lived absorption of the distorted cyclopropanone intermediate.
RESUMEN
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.
Asunto(s)
Morfinanos/química , Antagonistas de los Receptores de Orexina/química , Sulfonamidas/química , Conformación Molecular , Simulación de Dinámica Molecular , Estructura Molecular , Morfinanos/síntesis química , Antagonistas de los Receptores de Orexina/síntesis química , Estereoisomerismo , Sulfonamidas/síntesis químicaRESUMEN
The L-shaped, π-extended pentacycle dibenzopyrrolo[1,2-a][1,8]naphthyridine and its derivatives were synthesized using two methods: fully intramolecular [2 + 2 + 2] cycloaddition and oxidative aromatization using substituted carbodiimide and modification of an electron-rich indole ring of an L-shaped skeleton via electrophilic reaction and cross-coupling. These L-shaped compounds emitted fluorescence in high quantum yield. The position of substituents affected the fluorescence color through two different mechanisms, π-conjugation and skeletal distortion, which caused the substituted L-shaped compounds to emit fluorescence in a variety of colors and to exhibit solvato-fluorochromism.