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1.
Naoshi Yamamoto Sayaka Ohrui Takahiro Okada Masahiro Yata Tsuyoshi Saitoh Noriki Kutsumura Yasuyuki Nagumo Yoko Irukayama-Tomobe Yasuhiro Ogawa Yukiko Ishikawa Yurie Watanabe Daichi Hayakawa Hiroaki Gouda Masashi Yanagisawa Hiroshi Nagase 《Bioorganic & medicinal chemistry letters》2017,27(17):4176-4179
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 6β-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. 相似文献
2.
《Bioorganic & medicinal chemistry letters》2020,30(3):126893
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). 相似文献
3.
Sayaka Ohrui Naoshi Yamamoto Tsuyoshi Saitoh Noriki Kutsumura Yasuyuki Nagumo Yoko Irukayama-Tomobe Yasuhiro Ogawa Yukiko Ishikawa Yurie Watanabe Daichi Hayakawa Hiroaki Gouda Masashi Yanagisawa Hiroshi Nagase 《Bioorganic & medicinal chemistry letters》2018,28(4):774-777
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. 相似文献
4.
Naoshi Yamamoto Sayaka Ohrui Takahiro Okada Tsuyoshi Saitoh Noriki Kutsumura Yasuyuki Nagumo Yoko Irukayama-Tomobe Yasuhiro Ogawa Yukiko Ishikawa Yurie Watanabe Daichi Hayakawa Hiroaki Gouda Masashi Yanagisawa Hiroshi Nagase 《Bioorganic & medicinal chemistry》2019,27(8):1747-1758
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 6β-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 6β-derivatives. 相似文献
5.
《Bioorganic & medicinal chemistry letters》2020,30(17):127360
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. 相似文献
6.
Charles J. McElhinny Anita H. Lewin S. Wayne Mascarella Scott Runyon Lawrence Brieaddy F. Ivy Carroll 《Bioorganic & medicinal chemistry letters》2012,22(21):6661-6664
SB-334867 has been an important ligand for the study of the orexin 1 (OX1) receptor due to its high OX1/OX2 selectivity and bioavailability. This ligand however, contains a 2-methylbenzoxazole ring system which is known to undergo hydrolysis, particularly under acidic or basic conditions. The possibility that SB-334867 would be susceptible to significant hydrolysis was evaluated in various formulations and in the solid state. SB-334867 was found to be unstable under conditions commonly employed to prepare stock solutions for in vitro and in vivo studies. In addition, and most alarmingly, the hydrochloride salt of SB-334867 was found to quantitatively decompose to an OX1-inactive product even in the solid state. These findings combine to suggest that studies using SB-334867 (and any other 2-methylbenzoxazole-containing compound) should be performed with great care to avoid the confounding effects of the rapid hydrolytic decomposition of this susceptible structure. 相似文献
7.
Herein the effect of orexin receptor type-1 antagonist SB-334867 on the development of tolerance to analgesic effects of morphine was studied in rats. To incite tolerance, morphine sulfate was injected intraperitoneally (i.p., 10mg/kg) once a day for 7 days. The tail flick test was used to evaluate antinociceptive effects of the morphine. A selective OxR1 receptor antagonist, SB-334867, was microinjected (i.c.v.) into the right cerebral ventricle (10 μg/10 μl) immediately before each morphine injection. Repeated morphine application resulted in tolerance to morphine analgesic effects as a decreasing trend during 7 days. Also, repeated administration of SB-334867 (i.c.v.) alone was without significant effect on the nociception as compared to control. Microinjection of SB-334867 prior to each morphine injection inhibited the development of tolerance, so that the analgesic effects of morphine were significantly higher in SB-334867 plus morphine treated rats than that of vehicle plus morphine treated ones on days 4-7. It is concluded that orexin receptor type-1 might be involved in the development of tolerance to morphine analgesic effects. 相似文献
8.
Park HG Choi JY Choi SH Park MK Lee J Suh YG Cho H Oh U Lee J Kang SU Lee J Kim HD Park YH Su Jeong Y Kyu Choi J Jew SS 《Bioorganic & medicinal chemistry letters》2004,14(3):787-791
A series of N-4-substituted-benzyl-N'-tert-butylbenzyl thioureas were prepared for the study of their agonistic/antagonistic activities to the vanilloid receptor in rat DRG neurons. Their structure-activity relationship reveals that not only the two oxygens and amide hydrogen of sulfonamido group, but also the optimal size of methyl in methanesulfonamido group play an integral role for the antagonistic activity on vanilloid receptor. 相似文献
9.
With an aim to disclose the convergency and flexibility of our previously explored synthetic route to natural himbacine 1, and moreover, to clarify some novel aspects of the structure-activity relationships of 1, we prepared various structural types of novel himbacine congeners, 3-demethylhimbacine (3-norhimbacine) 2 and 4-epi-3-demethylhimbacine (4-epi-3-norhimbacine) 4-epi-2 and their enantiomers (ent-2 and ent-4-epi-2), 11-methylhimbacine 3, and 3-epihimbacine 4 in optically pure forms by employing our methodology. All of the synthesized congeners correspond to the compounds modified at the C-3 position of gamma-lactone moiety involved in 1. Among these congeners, 3-demethylhimbacine (3-norhimbacine) 2 was found to exhibit more potent muscarinic M(2) receptor binding affinity than natural 1. 相似文献
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12.
Robert L. Dow John R. Hadcock Dennis O. Scott Steven R. Schneider Ernest S. Paight Philip A. Iredale Philip A. Carpino David A. Griffith Marlys Hammond Paul DaSilva-Jardine 《Bioorganic & medicinal chemistry letters》2009,19(18):5351-5354
A new series of CB1 receptor antagonists incorporating an imidazole-based isosteric replacement for the hydrazide moiety of rimonabant (SR141716) is disclosed. Members of this imidazole series possess potent/selective binding to the rCB1 receptor and exhibit potent hCB1 functional activity. Isopropyl analog 9a demonstrated activity in the tetrad assay and was orally-active in a food intake model. 相似文献
13.
Miller GM 《Journal of neurochemistry》2011,116(2):164-176
It is now recognized that trace amine associated-receptor 1 (TAAR1) plays a functional role in the regulation of brain monoamines and the mediation of action of amphetamine-like psychostimulants. Accordingly, research on TAAR1 opens the door to a new avenue of approach for medications development to treat drug addiction as well as the spectrum of neuropsychiatric disorders hallmarked by aberrant regulation of brain monoamines. This overview focuses on recent studies which reveal a role for TAAR1 in the functional regulation of monoamine transporters and the neuronal regulatory mechanisms that modulate dopaminergic activity. 相似文献
14.
Ovariectomized rats were hormonally primed with 10 μg estradiol benzoate or with estradiol benzoate plus 500 μg progesterone. Rats received a bilateral infusion with 200 ng of the 5-HT1B/1D receptor antagonist, N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)-1-1′-biphenyl-4-carboxamide hydrochloride (GR 127935), into the ventromedial nucleus of the hypothalamus (VMN), followed by a 5 min restraint or home cage experience. In estrogen-primed females that had experienced minimal handling between ovariectomy and use in the experiment, infusion with the water vehicle transiently inhibited lordosis behavior, and the 5-HT1B/1D receptor antagonist amplified this inhibition. There were no effects in rats hormonally primed with estrogen and progesterone. Handling for two days before the experiment reduced the effects of the infusions in estrogen-primed rats. However, when a 5 min restraint experience followed infusion with GR 127935, there was a significant decline in lordosis behavior that persisted for 10 to 15 min after the experience. Regardless of the prior experience or type of infusion, the addition of progesterone to the hormonal priming completely prevented the lordosis inhibition. These findings are consistent with prior evidence that progesterone protects against the inhibitory effects of a 5 min restraint experience on lordosis behavior. Moreover, these are the first experiments to demonstrate an inhibitory effect of a selective 5-HT1B/1D receptor antagonist in the VMN on lordosis behavior of estrogen primed, but not estrogen and progesterone primed, ovariectomized rats. 相似文献
15.
Usuki Y Matsumoto K Inoue T Yoshioka K Iio H Tanaka T 《Bioorganic & medicinal chemistry letters》2006,16(6):1553-1556
Several N-methyl-N'-alkylguanidinium derivatives were synthesized and used as simplified analogues of niphimycin (NM), a guanidylpolyol macrolide, in structure-activity relationship studies. The C16-alkylated derivative exerted fungicidal activity by directly damaging the fungal plasma membrane and inducing oxidative stress in a manner similar to niphimycin. These results indicate that the N-methyl-N'-alkylguanidinium moiety is required for antifungal activity by NM. 相似文献
16.
Galanski ME Erker T Handler N Lemmens-Gruber R Kamyar M Studenik CR 《Bioorganic & medicinal chemistry》2006,14(3):826-836
A series of new nonpeptide vasopressin antagonists with a 6-ethyl-thieno[2,3-b][1,4]thiazine or 6-benzyl-thieno[2,3-b][1,4]thiazine skeleton and structural modifications of the aryl side chain were synthesized in this study. The effects on guinea pig heart and smooth muscle preparations were investigated. In the presence of AVP the compounds showed an antagonistic effect. The compounds did not change spontaneous rate in right atria and exerted a slight but not significant negative inotropic effect in papillary muscles. The relaxing effect on vascular smooth muscle and terminal ileum was far more pronounced. Generally the relaxing effect on terminal ilea was more potent maybe due to difference in V1a receptor density. Our results demonstrate that compounds with an ethyl group in position six on the thienothiazine ring (14, 16, 18 and 22) exerted the most potent relaxing activity in terminal ilea, whereas compounds with a phenyl ring in position six reduced this effect. 相似文献
17.
Tebas P Tuluc F Barrett JS Wagner W Kim D Zhao H Gonin R Korelitz J Douglas SD 《PloS one》2011,6(9):e24180
Background
Neurokinin-1 receptor (NK1R) antagonists have anti-HIV activity in monocyte-derived macrophages, decrease CCR5 expression and improve natural killer cell function ex vivo. Aprepitant is a NK1R antagonist approved by FDA as an antiemetic.Methods
We conducted a phase IB randomized, placebo controlled, double masked study to evaluate the safety, antiviral activity, pharmacokinetics and immune-modulatory effects of aprepitant in HIV-infected adults not receiving antiretroviral therapy, with CD4+ cell count ≥350 cells/mm3 and plasma viral load ≥2,000 copies/ml. Subjects were stratified by viral load (< vs. ≥20,000 copies/ml) and randomized within each stratum to receive aprepitant at 125 mg QD(Low), or 250 mg QD(High), or placebo(PL) for 14 days, and followed for 42 days.Results
Thirty subjects were randomized and 27 completed treatment (9, 8, 10 subjects in 125 (Low), 250 (High), and PL groups). 63% were male; 37% white; mean (SD) age 43 (9.3) years. Geometric mean baseline viral load (copies/ml) for Low, High, and PL was 15,709, 33,013, and 19,450, respectively. Mean (95%CI) change in log10 viral load at day 14 for Low, High, and PL was −0.02(−0.24,+0.20), −0.05(−0.21,+0.10), and +0.04(−0.08,+0.16), respectively. The number of subjects with AEs was 4(44.4%), 5(62.5%), and 1(10%) for Low, High, and PL. No Grade 4 AEs occurred.Conclusions
Adverse events of aprepitant were more common in the treated groups. At the dose used in this two-week phase IB study, aprepitant showed biological activity, but no significant antiviral activity.Trial Registration
ClinicalTrials.gov NCT00428519相似文献18.
Alexander Abazid Benedikt Martin Anja Choinowski Rhiannon V. McNeill Lars-Ove Brandenburg Patrick Ziegler Uwe Zimmermann Martin Burchardt Holger Erb Matthias B. Stope 《Journal of cellular biochemistry》2019,120(10):16711-16722
Enzalutamide's accepted mode of action is by targeting the androgen receptor's (AR) activity. In clinical practice, enzalutamide demonstrates a good benefit-risk profile for the treatment of advanced prostate cancer (PC), even after poor response to standard antihormonal treatment. However, since both, well-established antiandrogens and enzalutamide, target AR functionality, we hypothesized that additional unknown mechanisms might be responsible for enzalutamide's superior anticancer activity. In the current study, PC cells were incubated with enzalutamide and enzalutamide-dependent modulation of apoptotic mechanisms were assessed via Western blot analysis, TDT-mediated dUTP-biotin nick end-labeling assay, and nuclear morphology assay. Alterations of heat shock protein (HSP), AR, and estrogen receptor (ER) expression were examined by Western blot analysis. Enzalutamide attenuated the proliferation of PC cells in a time- and dose-dependent manner. In the presence of enzalutamide, apoptosis occurred which was shown by increased BAX expression, decreased Bcl-2 expression, nuclear pyknosis, and genomic DNA fragmentation. Moreover, enzalutamide inhibited the expression of HSPs primarily involved in steroid receptor stabilization and suppressed AR and ERβ1 expression. This study demonstrates for the first time that enzalutamide treatment of PC cells triggers varying molecular mechanisms resulting in antiproliferative effects of the drug. In addition to the well-characterized antagonistic inhibition of AR functionality, we have shown that enzalutamide also affects the intracellular synthesis of steroid receptor-associated HSPs, thereby diminishing the expression of AR and ERβ1 proteins and inducing apoptotic pathways. According to an indirect attenuation of HSP-associated factors such as steroid receptors, endometrial carcinoma, uterine leiomyosarcoma, and mamma carcinoma cells also demonstrated inhibited cell growth in the presence of enzalutamide. Our data, therefore, suggest that enzalutamide's high efficacy is at least partially independent of AR and p53 protein expression, which are frequently lost in advanced PC. 相似文献
19.
Katsumi Nogimori Kiyoshi Ito Makoto Tamura Soichiro Satoh Shinichi Ishii Michio Ui 《Biochimica et Biophysica Acta (BBA)/General Subjects》1984,801(2):220-231
Chemical modification of amino groups in the molecule of islet-activating protein (IAP), pertussis toxin, resulted in differential modification of biological activities of the toxin estimated in vivo with rats. Acetamidination of ε-amino groups of 50% (or more) of lysine residues in the IAP molecule totally abolished the lymphocytosis-promoting activity, but exerted no effects on the epinephrine-hyperglycemia inhibitory activity, of the toxin. Both activities were abolished by acylation of 50% or more of the amino groups probably due to the destruction of the toxin's quarternary structure. In contrast, the subunit assembly of IAP was maintained after exhaustive acetamidination of its lysine residues. The ADP-ribosyltranferase (or NAD-glycohydrolase) activity of the A-protomer (the biggest subunit) of IAP, which is responsible for the principal action of the toxin, enhancing insulin secretory responses and thereby inhibiting epinephrine hyperglycemia, was not affected by acetamidination of lysine residues. Thus, the A-protomer moiety of IAP is not directly involved in, but the amino groups of lysine residues in other subunits are selectively essential for, the development of the toxin-induced lymphocytosis. 相似文献
20.
The role of tyrosine kinase activity in endocytosis, compartmentation, and down-regulation of the epidermal growth factor receptor. 总被引:9,自引:0,他引:9
H S Wiley J J Herbst B J Walsh D A Lauffenburger M G Rosenfeld G N Gill 《The Journal of biological chemistry》1991,266(17):11083-11094
Occupancy-induced down-regulation of cell surface epidermal growth factor (EGF) receptors attenuates signal transduction. To define mechanisms through which down-regulation of this class of growth factor receptors occurs, we have investigated the relative roles of ligand-induced internalization and recycling in this process. Occupied, kinase-active EGF receptors were internalized through a high affinity, saturable endocytic system at rates up to 10-fold faster than empty receptors. In contrast, full length EGF receptors lacking tyrosine kinase activity underwent internalization at a rate independent of occupancy. This "kinase-independent" internalization rate appeared to reflect constitutive receptor internalization since it was similar to the internalization rate of both receptors lacking a cytoplasmic domain and of antibodies bound to empty receptors. EGF internalized by either kinase-active or kinase-inactive receptors was efficiently recycled and was found within endosomes containing recycling transferrin receptors. However, targeting of internalized receptors to lysosomes did not require receptor kinase activity. All receptors that displayed ligand-induced internalization also underwent down-regulation, indicating that the proximal cause of down-regulation is occupancy-induced endocytosis. Tyrosine kinase activity greatly enhances this process by stabilizing receptor association with the endocytic apparatus. 相似文献