共查询到20条相似文献,搜索用时 0 毫秒
1.
《Bioorganic & medicinal chemistry letters》2019,29(15):1938-1942
We discovered a novel compound, 5-methyl-1,4,5,7-tetrahydro-2,5-ethanoazocino[4,3-b]indol-6(3H)-one sulfuric acid salt (DS39201083), which was formed by derivatization of a natural product, conolidine. DS39201083 had a unique bicyclic skeleton and was a more potent analgesic than conolidine, as revealed in the acetic acid-induced writhing test and formalin test in ddY mice. The compound showed no agonist activity at the mu opioid receptor. 相似文献
2.
Weltrowska G Lu Y Lemieux C Chung NN Schiller PW 《Bioorganic & medicinal chemistry letters》2004,14(18):4731-4733
2',6'-Dimethyl substitution of the Tyr(1) residue in opioid agonist peptides and deletion of the N-terminal amino group, as achieved by replacement of Tyr(1) with 3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid (Dhp), have been shown to produce opioid antagonists. To examine the effect of beta-methylation of Dhp(1) in opioid peptides on the activity profile, stereoselective syntheses of (3S)- and (3R)-3-methyl-3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid [(3S)- and (3R)-Mdp] were carried out. In comparison with the cyclic parent antagonist peptide Dhp-c[D-Cys-Gly-Phe(pNO(2))-D-Cys]NH(2), the methylated analogue (3S)-Mdp-c[D-Cys-Gly-Phe(pNO(2))-D-Cys]NH(2) showed higher micro, delta and kappa antagonist potencies in functional assays and higher binding affinities for micro, delta and kappa opioid receptors (K(i)(micro)=2.03 nM; K(i)(delta)=2.34 nM; K(i)(kappa)=49.5 nM), whereas the corresponding (3R)-Mdp(1)-analogue was less potent by 1-2 orders of magnitude. 相似文献
3.
《Bioorganic & medicinal chemistry》2020,28(21):115714
We identified (5′S)-10′-fluoro-6′-methyl-5′,6′-dihydro-3′H-spiro[cyclopropane-1,4′-[2,6]diaza[2,5]methano[2,6]benzodiazonin]-7′(1′H)-one, 22b (DS34942424) with a unique and original bicyclic skeleton. 22b showed an orally potent analgesic in the acetic acid-induced writhing test and formalin test in ddY mice without sedation. Moreover, 22b did not exhibit mu opioid receptor agonist activity. 相似文献
4.
The morphiceptin-derived peptide [Dmt1, d-1-Nal3]morphiceptin, labeled mu-opioid receptor (MOP) with very high affinity and selectivity in the receptor binding assays. In the mouse hot plate test, [Dmt1, d-1-Nal3]morphiceptin given intracerebroventricularly (i.c.v.) produced profound supraspinal analgesia, being approximately 100-fold more potent than the endogenous MOP receptor ligand, endomorphin-2. The antinociceptive effect of this new analog lasted up to 120min. Thus, [Dmt1, d-1-Nal3]morphiceptin is an interesting and extraordinarily potent analgesic, raising the possibility of novel approaches in the design of clinically useful drugs for pain treatment. 相似文献
5.
Tsuyoshi Arita Masayoshi Asano Kazufumi Kubota Yuki Domon Nobuo Machinaga Kousei Shimada 《Bioorganic & medicinal chemistry letters》2019,29(23):126748
We synthesized derivatives of a natural alkaloid, conolidine, and evaluated these derivatives in the acetic acid-induced writhing test and formalin test in ddY mice after oral administration. As a result, we identified (5S)-6-methyl-1,3,4,5,6,8-hexahydro-7H-2,5-methano[1,5]diazonino[7,8-b]indol-7-one sulfate salt, 15a (DS54360155), with a unique and original bicyclic skeleton, as an analgesic more potent than conolidine. Moreover, 15a did not exhibit mu-opioid receptor agonist activity. 相似文献
6.
Elephant beta-endorphin and its analog, elephant beta-endorphin(6-31) were synthesized by standard solid phase method. Receptor binding activity showed that elephant beta-endorphin was five to six times more potent than human beta-endorphin in its ability to bind to opiate receptors on rat brain membrane. In a previous study (Wong, C.-L., Wai, M.-K., Cheng, H.-C., Chung, D. & Yamashiro, D (1990) Clinical and Experimental Pharmacology and Physiology 16, 33-37), tail flick test for intracerebroventricularly administered beta-endorphin showed that the antinociceptive potency of elephant beta-endorphin was seven to eight times higher than that of human beta-endorphin in mice. Results from both studies suggest that elephant beta-endorphin was a much more potent antinociceptive agent than human beta-endorphin in tail flick test and its higher analgesic activity might be due to its higher affinity for opiate receptors in the brain. 相似文献
7.
A new class of high affinity opioid and opioid receptor-like receptor (ORL1 receptor, NOP receptor) ligands has been designed by conformational restriction of piperidine-based NOP receptor ligands, resulting in a novel quinolizidine scaffold. Different modifications of the pendant functional groups on the scaffold provide differential activities at the opioid and NOP receptors. While the conformational rigidity will provide an improved understanding of the NOP and opioid receptor binding pockets, these compounds also provide a new template for the design of novel opiate and NOP ligands. 相似文献
8.
Sakami S Kawai K Maeda M Aoki T Fujii H Ohno H Ito T Saitoh A Nakao K Izumimoto N Matsuura H Endo T Ueno S Natsume K Nagase H 《Bioorganic & medicinal chemistry》2008,16(17):7956-7967
We have previously reported on antitussive effect of (5R,9R,13S,14S)-17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5',6'-dihydro-3-methoxy-4'H-pyrrolo[3,2,1-ij]quinolino[2',1':6,7]morphinan-14-ol(1b) methanesulfonate (TRK-850), a selective delta opioid receptor antagonist which markedly reduced the number of coughs in a rat cough model. We designed TRK-850 based on naltrindole (NTI), a typical delta opioid receptor antagonist, to improve its permeability through the blood-brain barrier by introducing hydrophobic moieties to NTI. The ED(50) values of NTI and compound 1b by intraperitoneal injections were 104 microg/kg and 2.07 microg/kg, respectively. This increased antitussive potency probably resulted from the improved brain exposure of compound 1b. However, 1b was extremely unstable toward metabolism by cytochrome P450. In this study, we designed and synthesized compound 1b derivatives to improve the metabolic instability, which resulted in affording highly potent and metabolically stable oral antitussive agent (5R,9R,13S,14S)-17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-8'-fluoro-5',6'-dihydro-4'H-pyrrolo[3,2,1-ij]quinolino[2',1':6,7]morphinan-3,14-diol (1c) methanesulfonate (TRK-851). 相似文献
9.
Yasuda Y Li Z Greenbaum D Bogyo M Weber E Brömme D 《The Journal of biological chemistry》2004,279(35):36761-36770
Atherosclerosis is characterized by a thickening and loss of elasticity of the arterial wall. Loss of elasticity has been attributed to the degradation of the arterial elastin matrix. Cathepsins K and S are papain-like cysteine proteases with known elastolytic activities, and both enzymes have been identified in macrophages present in plaque areas of diseased blood vessels. Here we demonstrate that macrophages express a third elastolytic cysteine protease, cathepsin V, which exhibits the most potent elastase activity yet described among human proteases and that cathepsin V is present in atherosclerotic plaque specimens. Approximately 60% of the total elastolytic activity of macrophages can be attributed to cysteine proteases with cathepsins V, K, and S contributing equally. From this 60%, two-thirds occur extracellularly and one-third intracellularly with the latter credited to cathepsin V. Ubiquitously expressed glycosaminoglycans (GAGs) such as chondroitin sulfate specifically inhibit the elastolytic activities of cathepsins V and K via the formation of specific cathepsin-GAG complexes. In contrast, cathepsin S, which does not form complexes with chondroitin sulfate is not inhibited; thus suggesting a specific regulation of elastolytic activities of cathepsins by GAGs. Because the GAG content is reduced in atherosclerotic plaques, an increase of cathepsins V and K activities may accelerate the destruction of the elastin matrix in diseased arteries. 相似文献
10.
Chaturvedi K 《Indian journal of experimental biology》2003,41(1):5-13
Biogenesis of various endogenous opioid peptides, anatomical distribution and the characteristics of multiple receptors with which they interact provides an opportunity for understanding the role of opioid systems and mechanism of opioid tolerance. Cellular and anatomical distribution of opioid receptor and their function is important for identification of neuronal systems and local network involved in initiation of drug action and subsequent development of adaptations resulting from repeated drug use. The details concerning discovery and progress in endogenous opioid peptide research and their distribution in brain have been described in this review. This review also describes opioid receptors, their distribution and mechanism of down regulation, which may be one of the causes for tolerance to opioids. Agonist induced down regulation and recent evidence for involvement of ubiquitin/proteasome system in this process has been discussed. 相似文献
11.
《Bioorganic & medicinal chemistry letters》2014,24(15):3430-3433
The synthesis and biological evaluation of a novel pyridinium salt is reported. Initial membrane interaction with isolated phospholipid monolayers was obtained with the pyridinium salt, and two neutral analogues for comparison, and the anticancer effects of the best compound established using a cytotoxicity screening assay against glioma cells using both an established cell line and three short-term cell cultures—one of which has been largely resistant to all chemotherapeutic drugs tested to date. The results indicate that the pyridinium salt exhibits potent anticancer activity (EC50s = 9.8–312.5 μM) on all cell types, including the resistant one, for a continuous treatment of 72 h. Microscopic examination of the treated cells using a trypan blue exclusion assay showed membrane lysis had occurred. Therefore, this letter highlights the potential for a new class of pyridinium salt to be developed as a much needed alternative treatment for glioma chemotherapy. 相似文献
12.
13.
A W Lipkowski A Misicka P Davis D Stropova J Janders M Lachwa F Porreca H I Yamamura V J Hruby 《Bioorganic & medicinal chemistry letters》1999,9(18):2763-2766
The synthesis and biological activity of two fragments of the very potent opioid peptide biphalin, showed that Tyr-D-Ala-Gly-Phe-NH-NH<-Phe is the minimal fragment necessary to express equal affinities and the same biological activity profile as the parent biphalin. The replacement of N'-Phe with other L- or D- lipophilic amino acids showed the possibility of modification of receptor efficacy of the analogues. 相似文献
14.
Wen-Qun Li Xu-Li Wang Keduo Qian Ying-Qian Liu Chih-Ya Wang Liu Yang Jin Tian Susan L. Morris-Natschke Xing-Wen Zhou Kuo-Hsiung Lee 《Bioorganic & medicinal chemistry》2013,21(8):2363-2369
Twenty new acyl thiourea derivatives of podophyllotoxin and 4′-demethylepipodophyllotoxin were prepared and screened for their cytotoxicity against four human tumor cell lines, A-549, DU-145, KB, and KBvin. With IC50 values of 0.098–1.13 μM, compounds 13b, 13c, and 13o displayed much better cytotoxic activity than the control etoposide. Most importantly, 13b and 13o exhibited promising cytotoxicity against the drug resistant tumor cell line KBvin with IC50 values of 0.098 and 0.13 μM, respectively, while etoposide lost activity completely. Structure–activity relationship (SAR) correlations of the new derivatives have been established. Compounds 13b and 13o merit further development as a new generation of epipodophyllotoxin-derived antitumor clinical trial candidates. 相似文献
15.
Konno K Picolo G Gutierrez VP Brigatte P Zambelli VO Camargo AC Cury Y 《Peptides》2008,29(8):1293-1304
We have shown that the venom of the South American rattlesnake Crotalus durissus terrificus induces a long-lasting antinociceptive effect mediated by activation of kappa- and delta-opioid receptors. Despite being mediated by opioid receptors, prolonged treatment with the crotalid venom does not cause the development of peripheral tolerance or abstinence symptoms upon withdrawal. In the present study, we have isolated and chemically characterized a novel and potent antinociceptive peptide responsible for the oral opioid activity of this crotalid venom. The amino acid sequence of this peptide, designated crotalphine, was determined by mass spectrometry and corroborated by solid-phase synthesis to be 相似文献
16.
17.
The interaction of metkephamid (Tyr-D-Ala-Gly-Phe-N(Me)Met-NH2) with 3H-dihydromorphine and 3H-D-Ala2-D-Leu5-enkephalin binding has been examined in rat brain homogenates. Displacements of both 3H-ligands by metkephamid indicate that metkephamid interacts competitively with greatest potency to the high affinity binding component for both ligands (mu1 site). Unlike most enkephalins and opiates, metkephamid binds equipotently to both morphine-selective (mu2) and enkephalin-selective (delta) binding sites. Metkephamid is differentiated from morphine by its better than 12-fold higher affinity for the delta receptor. Blockade of the high affinity (mu1) binding in vivo with high doses of naloxazone dramatically reduces metkephamid's analgesic potency. 相似文献
18.
Morphine, enkephalins, nalorphine, naloxone and pentazocine are shown to have a peripheral analgesic effect. In our modification of the Randall-Selitto test these substances were 50–100 times more potent than a standard local anaesthetic, lidocaine. At this peripheral site, naloxone did not antagonize the effect of morphine. Morphine had a marked analgesic effect on the hyperalgesia induced by PGE2 and PGI2, BaCl2, Ca2+ ionophore A23187, isoprenaline but not on that induced by dibutyryl cyclic AMP. It was suggested that the peripheral analgesic effect of morphine is due to an inhibition of adenylate-cyclase activity. 相似文献
19.
The introduction of the Dmt (2',6'-dimethyl-L-tyrosine)-Tic pharmacophore into the design of opioid ligands produced an extraordinary family of potent delta-opioid receptor antagonists and heralded a new phase in opioid research. First reviewed extensively in 1998, the incorporation of Dmt into a diverse group of opioid molecules stimulated the opioid field leading to the development of unique analogues with remarkable properties. This overview will document the crucial role played by this residue in the proliferation of opioid peptides with high receptor affinity (K(i) equal to or less than 1 nM) and potent bioactivity. The discussion will include the metamorphosis between delta-opioid receptor antagonists to delta-agonists based solely on subtle structural changes at the C-terminal region of the Dmt-Tic pharmacophore as well as their behavior in vivo. Dmt may be considered promiscuous due to the acquisition of potent mu-agonism by dermorphin and endomorphin derivatives as well as by a unique class of opioidmimetics containing two Dmt residues separated by alkyl or pyrazinone linkers. Structural studies on the Dmt-Tic compounds were enhanced tremendously by x-ray diffraction data for three potent and biologically diverse Dmt-Tic opioidmimetics that led to the development of pharmacophores for both delta-opioid receptor agonists and antagonists. Molecular modeling studies of other unique Dmt opioid analogues illuminated structural differences between delta- and mu-receptor ligand interactions. The future of these compounds as therapeutic applications for various medical syndromes including the control of cancer-associated pain is only a matter of time and perseverance. 相似文献
20.
Maruyama T Yamamoto Y Kano Y Kurazono M Matsuhisa E Takata H Takata T Atsumi K Iwamatsu K Shitara E 《Bioorganic & medicinal chemistry》2007,15(19):6379-6387
A new series of 1beta-methyl carbapenems possessing a 6,7-disubstituted imidazo[5,1-b]thiazol-2-yl group directly attached to the C-2 position of the carbapenem nucleus was prepared, and the activities of these compounds against methicillin-resistant Staphylococcus aureus (MRSA) were evaluated. To study the effect of basic moieties on anti-MRSA activity, we introduced an amino, or imino, or amidino group at the 6-position of imidazo[5,1-b]thiazole in place of the carbamoylmethyl moiety of CP5068. Anti-MRSA activities of almost all basic group-substituted carbapenems were improved, though some of the compounds showed stronger acute toxicity in mice than IPM. In order to decrease the toxicity without decreasing the activity, we introduced various additional functionalities around the basic moiety. Finally, we obtained CP5484, which has excellent anti-MRSA activity and low acute toxicity. 相似文献