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1.
Eur J Med Chem ; 159: 74-89, 2018 Nov 05.
Article in English | MEDLINE | ID: mdl-30268825

ABSTRACT

Small molecules that target microtubules (MTs) represent promising therapeutics to treat certain types of cancer, including glioblastoma multiform (GBM). We synthesized modified carbazoles and evaluated their antitumor activity in GBM cells in culture. Modified carbazoles with an ethyl moiety linked to the nitrogen of the carbazole and a carbonyl moiety linked to distinct biaromatic rings exhibited remarkably different killing activities in human GBM cell lines and patient-derived GBM cells, with IC50 values from 67 to >10,000 nM. Measures of the activity of modified carbazoles with tubulin and microtubules coupled to molecular docking studies show that these compounds bind to the colchicine site of tubulin in a unique low interaction space that inhibits tubulin assembly. The modified carbazoles reported here represent novel chemical tools to better understand how small molecules disrupt MT functions and kill devastating cancers such as GBM.


Subject(s)
Antineoplastic Agents/pharmacology , Carbazoles/pharmacology , Glioblastoma/drug therapy , Microtubules/drug effects , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Carbazoles/chemical synthesis , Carbazoles/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Glioblastoma/pathology , Humans , Molecular Docking Simulation , Molecular Structure , Structure-Activity Relationship
2.
ACS Chem Neurosci ; 6(2): 277-87, 2015 Feb 18.
Article in English | MEDLINE | ID: mdl-25314588

ABSTRACT

Low-voltage-activated (T-type) calcium channels are important regulators of the transmission of nociceptive information in the primary afferent pathway and finding ligands that modulate these channels is a key focus of the drug discovery field. Recently, we characterized a set of novel compounds with mixed cannabinoid receptor/T-type channel blocking activity and examined their analgesic effects in animal models of pain. Here, we have built on these previous findings and synthesized a new series of small organic compounds. We then screened them using whole-cell voltage clamp techniques to identify the most potent T-type calcium channel inhibitors. The two most potent blockers (compounds 9 and 10) were then characterized using radioligand binding assays to determine their affinity for CB1 and CB2 receptors. The structure-activity relationship and optimization studies have led to the discovery of a new T-type calcium channel blocker, compound 9. Compound 9 was efficacious in mediating analgesia in mouse models of acute inflammatory pain and in reducing tactile allodynia in the partial nerve ligation model. This compound was shown to be ineffective in Cav3.2 T-type calcium channel null mice at therapeutically relevant concentrations, and it caused no significant motor deficits in open field tests. Taken together, our data reveal a novel class of compounds whose physiological and therapeutic actions are mediated through block of Cav3.2 calcium channels.


Subject(s)
Analgesics/pharmacology , Calcium Channel Blockers/pharmacology , Cannabinoid Receptor Antagonists/pharmacology , Analgesics/chemistry , Animals , Calcium Channel Blockers/chemistry , Calcium Channels, T-Type/genetics , Calcium Channels, T-Type/metabolism , Cannabinoid Receptor Antagonists/chemistry , Cell Line , Disease Models, Animal , Dose-Response Relationship, Drug , Humans , Hyperalgesia/drug therapy , Hyperalgesia/physiopathology , Male , Mice, Inbred C57BL , Mice, Knockout , Motor Activity/drug effects , Motor Activity/physiology , Pain/drug therapy , Pain/physiopathology , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB2/antagonists & inhibitors , Receptor, Cannabinoid, CB2/metabolism , Sciatic Nerve/injuries , Touch
3.
Mol Pain ; 10: 77, 2014 Dec 06.
Article in English | MEDLINE | ID: mdl-25481027

ABSTRACT

BACKGROUND: T-type calcium channels and cannabinoid receptors are known to play important roles in chronic pain, making them attractive therapeutic targets. We recently reported on the design, synthesis and analgesic properties of a novel T-type channel inhibitor (NMP-7), which also shows mixed agonist activity on CB1 and CB2 receptors in vitro. Here, we analyzed the analgesic effect of systemically delivered NMP-7 (intraperitoneal (i.p.) or intragstric (i.g.) routes) on mechanical hypersensitivity in inflammatory pain induced by Complete Freund's Adjuvant (CFA) and neuropathic pain induced by sciatic nerve injury. RESULTS: NMP-7 delivered by either i.p. or i.g. routes produced dose-dependent inhibition of mechanical hyperalgesia in mouse models of inflammatory and neuropathic pain, without altering spontaneous locomotor activity in the open-field test at the highest active dose. Neither i.p. nor i.g. treatment reduced peripheral inflammation per se, as evaluated by examining paw edema and myeloperoxidase activity. The antinociception produced by NMP-7 in the CFA test was completely abolished in CaV3.2-null mice, confirming CaV3.2 as a key target. The analgesic action of intraperitoneally delivered NMP-7 was not affected by pretreatment of mice with the CB1 antagonist AM281, but was significantly attenuated by pretreatment with the CB2 antagonist AM630, suggesting that CB2 receptors, but not CB1 receptors are involved in the action of NMP-7 in vivo. CONCLUSIONS: Overall, our work shows that NMP-7 mediates a significant analgesic effect in a model of persistent inflammatory and chronic neuropathic pain by way of T-type channel modulation and CB2 receptor activation. Thus, this study provides a novel therapeutic avenue for managing chronic pain conditions via mixed CB ligands/T-type channel blockers.


Subject(s)
Calcium Channels, T-Type/metabolism , Carbazoles/chemistry , Inflammation/metabolism , Neuralgia/drug therapy , Receptor, Cannabinoid, CB2/metabolism , Analgesia/methods , Analgesics/chemistry , Animals , Body Weight , Carbazoles/pharmacology , Freund's Adjuvant/metabolism , Hyperalgesia , Inflammation/drug therapy , Ligands , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Neuralgia/metabolism , Pain/drug therapy , Pain Measurement , Sciatic Nerve/injuries
4.
Eur J Med Chem ; 69: 881-907, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24125850

ABSTRACT

There is growing interest in using cannabinoid receptor 2 (CB2) agonists for the treatment of neuropathic pain and other indications. In continuation of our ongoing program aiming for the development of new small molecule cannabinoid ligands, we have synthesized a novel series of carbazole and γ-carboline derivatives. The affinities of the newly synthesized compounds were determined by a competitive radioligand displacement assay for human CB2 cannabinoid receptor and rat CB1 cannabinoid receptor. Functional activity and selectivity at human CB1 and CB2 receptors were characterized using receptor internalization and [(35)S]GTP-γ-S assays. The structure-activity relationship and optimization studies of the carbazole series have led to the discovery of a non-selective CB1 and CB2 agonist, compound 4. Our subsequent research efforts to increase CB2 selectivity of this lead compound have led to the discovery of CB2 selective compound 64, which robustly internalized CB2 receptors. Compound 64 had potent inhibitory effects on pain hypersensitivity in a rat model of neuropathic pain. Other potent and CB2 receptor-selective compounds, including compounds 63 and 68, and a selective CB1 agonist, compound 74 were also discovered. In addition, we identified the CB2 ligand 35 which failed to promote CB2 receptor internalization and inhibited compound CP55,940-induced CB2 internalization despite a high CB2 receptor affinity. The present study provides novel tricyclic series as a starting point for further investigations of CB2 pharmacology and pain treatment.


Subject(s)
Carbazoles/chemistry , Carbazoles/pharmacology , Neuralgia/drug therapy , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB2/agonists , Animals , Carbazoles/chemical synthesis , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Rats , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB2/metabolism , Structure-Activity Relationship
5.
Mol Pain ; 9: 32, 2013 Jul 01.
Article in English | MEDLINE | ID: mdl-23815854

ABSTRACT

BACKGROUND: Cannabinoid receptors and T-type calcium channels are potential targets for treating pain. Here we report on the design, synthesis and analgesic properties of a new mixed cannabinoid/T-type channel ligand, NMP-181. RESULTS: NMP-181 action on CB1 and CB2 receptors was characterized in radioligand binding and in vitro GTPγ[35S] functional assays, and block of transiently expressed human Cav3.2 T-type channels by NMP-181 was analyzed by patch clamp. The analgesic effects and in vivo mechanism of action of NMP-181 delivered spinally or systemically were analyzed in formalin and CFA mouse models of pain. NMP-181 inhibited peak CaV3.2 currents with IC50 values in the low micromolar range and acted as a CB2 agonist. Inactivated state dependence further augmented the inhibitory action of NMP-181. NMP-181 produced a dose-dependent antinociceptive effect when administered either spinally or systemically in both phases of the formalin test. Both i.t. and i.p. treatment of mice with NMP-181 reversed the mechanical hyperalgesia induced by CFA injection. NMP-181 showed no antinocieptive effect in CaV3.2 null mice. The antinociceptive effect of intrathecally delivered NMP-181 in the formalin test was reversed by i.t. treatment of mice with AM-630 (CB2 antagonist). In contrast, the NMP-181-induced antinociception was not affected by treatment of mice with AM-281 (CB1 antagonist). CONCLUSIONS: Our work shows that both T-type channels as well as CB2 receptors play a role in the antinociceptive action of NMP-181, and also provides a novel avenue for suppressing chronic pain through novel mixed T-type/cannabinoid receptor ligands.


Subject(s)
Analgesics/pharmacology , Calcium Channels, T-Type/metabolism , Carbazoles/pharmacology , Receptor, Cannabinoid, CB2/agonists , Analgesics/chemistry , Animals , CHO Cells , Calcium Channels, T-Type/genetics , Carbazoles/chemistry , Cricetulus , HEK293 Cells , Humans , Male , Mice , Mice, Knockout , Morpholines , Pain Measurement , Pyrazoles , Receptor, Cannabinoid, CB2/metabolism
6.
Bioorg Med Chem Lett ; 23(11): 3434-7, 2013 Jun 01.
Article in English | MEDLINE | ID: mdl-23623418

ABSTRACT

We report here the design, synthesis, and in vitro characterization of new opioid peptides featuring a 4-anilidopiperidine moiety. Despite the fact that the chemical structures of fentanyl surrogates have been found suboptimal per se for the opioid activity, the corresponding conjugates with opioid peptides displayed potent opioid activity. These studies shed an instructive light on the strategies and potential therapeutic values of anchoring the 4-anilidopiperidine scaffold to different classes of opioid peptides.


Subject(s)
Opioid Peptides/chemistry , Piperidines/chemistry , Animals , Cell Line , Fentanyl/chemistry , Humans , Kinetics , Mice , Opioid Peptides/chemical synthesis , Opioid Peptides/metabolism , Piperidines/chemical synthesis , Piperidines/metabolism , Protein Binding , Receptors, Opioid, delta/chemistry , Receptors, Opioid, delta/genetics , Receptors, Opioid, delta/metabolism , Receptors, Opioid, mu/chemistry , Receptors, Opioid, mu/genetics , Receptors, Opioid, mu/metabolism , Structure-Activity Relationship
7.
Mol Pain ; 7: 89, 2011 Nov 17.
Article in English | MEDLINE | ID: mdl-22093952

ABSTRACT

BACKGROUND: Both T-type calcium channels and cannabinoid receptors modulate signalling in the primary afferent pain pathway. Here, we investigate the analgesics activities of a series of novel cannabinoid receptor ligands with T-type calcium channel blocking activity. RESULTS: Novel compounds were characterized in radioligand binding assays and in vitro functional assays at human and rat CB1 and CB2 receptors. The inhibitory effects of these compounds on transient expressed human T-type calcium channels were examined in tsA-201 cells using standard whole-cell voltage clamp techniques, and their analgesic effects in response to various administration routes (intrathecally, intraplantarly, intraperitoneally) assessed in the formalin model. A series of compounds were synthesized and evaluated for channel and receptor activity. Compound NMP-7 acted as non-selective CB1/CB2 agonist while NMP4 was found to be a CB1 partial agonist and CB2 inverse agonist. Furthermore, NMP-144 behaved as a selective CB2 inverse agonist. All of these three compounds completely inhibited peak Cav3.2 currents with IC50 values in the low micromolar range. All compounds mediated analgesic effects in the formalin model, but depending on the route of administration, could differentially affect phase 1 and phase 2 of the formalin response. CONCLUSIONS: Our results reveal that a set of novel cannabinioid receptor ligands potently inhibit T-type calcium channels and show analgesic effects in vivo. Our findings suggest possible novel means of mediating pain relief through mixed T-type/cannabinoid receptor ligands.


Subject(s)
Analgesics/metabolism , Calcium Channels, T-Type/metabolism , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB2/metabolism , Analgesics/administration & dosage , Analgesics/pharmacology , Animals , CHO Cells , Carbazoles/metabolism , Carbazoles/pharmacology , Carbolines/metabolism , Carbolines/pharmacology , Cricetinae , Cricetulus , HEK293 Cells , Humans , Ligands , Rats , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Receptor, Cannabinoid, CB2/antagonists & inhibitors
8.
Bioorg Med Chem Lett ; 21(19): 5859-62, 2011 Oct 01.
Article in English | MEDLINE | ID: mdl-21855337

ABSTRACT

Cannabinoid CB2 receptor has emerged as a very promising target over the last decades. We have synthesized and evaluated a new fluorescent probe designated NMP6 based on 6-methoxyisatin scaffold, which exhibited selectivity and K(i) value at hCB2 of 387 nM. We have demonstrated its ability to be an effective probe for visualization of CB2 receptor binding using confocal microscopy and a flow cytometry probe for the analysis of CB2 protein expression. Furthermore, NMP6 was easily obtained in two chemical steps from commercially available building blocks.


Subject(s)
Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/metabolism , Hydrazones/chemical synthesis , Hydrazones/metabolism , Isatin/analogs & derivatives , Receptor, Cannabinoid, CB2/analysis , Animals , B-Lymphocytes , CHO Cells , Cricetinae , Drug Design , Drug Evaluation, Preclinical , Fluorescence , Fluorescent Dyes/chemistry , Humans , Hydrazines/chemistry , Hydrazines/metabolism , Hydrazones/chemistry , Isatin/chemical synthesis , Isatin/chemistry , Isatin/metabolism , Ligands , Lung , Mice , Mice, Inbred BALB C , Microscopy, Confocal , Molecular Structure , Oxadiazoles/chemistry , Oxadiazoles/metabolism , Protein Binding , Pyrans/pharmacology , Pyrimidines/pharmacology , Receptor, Cannabinoid, CB2/agonists , Receptor, Cannabinoid, CB2/metabolism , Structure-Activity Relationship
9.
Bioconjug Chem ; 20(9): 1711-5, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19689127

ABSTRACT

A persulfated molecular umbrella derived from one spermine, four lysine, and eight deoxycholic acid molecules was found to exhibit ionophoric activity, as shown by pH discharge and Na(+) and Cl(-) transport experiments. In sharp contrast, a moderately more hydrophilic analogue derived from cholic acid showed no such ionophoric activity. Both molecular umbrellas crossed liposomal membranes by passive transport with experimental rates that were similar. These findings show how the interactions between such amphomorphic molecules and phospholipid bilayers are a sensitive function of the umbrella's hydrophilic/lipophilic balance (HLB). They also raise the possibility of exploiting molecular umbrellas in fundamentally new ways.


Subject(s)
Deoxycholic Acid/chemistry , Ionophores/chemical synthesis , Lysine/chemistry , Spermine/chemistry , Biological Transport , Chlorides/metabolism , Hydrogen-Ion Concentration , Hydrophobic and Hydrophilic Interactions , Kinetics , Liposomes , Sodium/metabolism
10.
Bioconjug Chem ; 20(5): 1037-43, 2009 May 20.
Article in English | MEDLINE | ID: mdl-19374405

ABSTRACT

A homologous series of pore-forming amphiphiles (PFAs), derived from cholic acid, lysine, and spermine, have been used as "thermal gates" for releasing sucrose from liposomes made from 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (sodium salt) [DPPG]. Binding measurements have established that these PFAs are fully bound to these liposomes in their gel state and that their transfer to fluid phase membranes is negligible. Release experiments have shown that thermal gating is sensitive to both the size and the concentration of the PFA that are used. Increases in the extent of release of sucrose with increasing temperature that have been found in the gel/fluid coexistence region indicate the existence of heterogeneity among the liposomes.


Subject(s)
Liposomes/chemistry , Temperature , Cholic Acid/chemistry , Gels , Hydrophobic and Hydrophilic Interactions , Kinetics , Lysine/chemistry , Phase Transition , Porosity , Spermine/chemistry , Sucrose/metabolism
11.
Tetrahedron Lett ; 49(14): 2316-2319, 2008 Mar 31.
Article in English | MEDLINE | ID: mdl-19340283

ABSTRACT

A substituted hydropyrazino[1,2-a]pyrimidin-6-one derivative was synthesized stereoselectively via the intramolecular N-acyliminium ion cyclization between an amide nitrogen and an N(α)-acetal derived from Cbz-protected aminopropyl-phenylalaninamide in very good yields. The formation of a single diastereomer is due to the low energy chairlike conformation of its bicyclic structure. This methodology provides a convenient tool to build internal bicyclic peptidomimetics.

12.
Bioorg Med Chem Lett ; 16(20): 5462-7, 2006 Oct 15.
Article in English | MEDLINE | ID: mdl-16931008

ABSTRACT

A new bicyclic template has been developed for the synthesis of peptide mimetics. Straightforward synthetic steps, starting from amino acids, allow the facile construction of a wide range of analogs. This system was designed to target the melanocortin receptors (MCRs), with functional group selection based on a known pharmacophore and guidance from molecular modeling to rationally identify positional and stereochemical isomers likely to be active. The functions of hMCRs are critical to myriad biological activities, including pigmentation, steroidogenesis, energy homeostasis, erectile activity, and inflammation. These G-protein-coupled receptors (GPCRs) are targets for drug discovery in a number of areas, including cancer, pain, and obesity therapeutics. All compounds from this series tested to date are antagonists which bind with high affinity. Importantly, many are highly selective for a particular MCR subtype, including some of the first completely hMC5R-selective antagonists reported.


Subject(s)
Molecular Mimicry , Peptides/classification , Peptides/pharmacology , Receptors, Melanocortin/drug effects , Binding Sites , Cell Line , Drug Design , Drug Evaluation, Preclinical , Humans , Magnetic Resonance Spectroscopy/methods , Models, Molecular , Molecular Conformation , Peptides/chemistry , Sensitivity and Specificity , Stereoisomerism , Structure-Activity Relationship
13.
Bioorg Med Chem Lett ; 16(18): 4946-50, 2006 Sep 15.
Article in English | MEDLINE | ID: mdl-16828552

ABSTRACT

An enkephalin analogue coupled to 'aminofentanyl' has been synthesized and tested for biological activities at the mu and delta opioid receptors. Aminofentanyl which represents a structural derivative of fentanyl has been synthesized by acylation of 1-(2-phenethyl)-4-(N-anilino)piperidine with phthaloyl protected beta-alaninyl chloride in the presence of DIPEA, followed by deprotection with hydrazine hydrate. Aminofentanyl has also been successfully acylated with ethyl isocyanate, various acid anhydrides, to further investigate structure-activity relationships of these new fentanyl derivatives. Among the new derivatives compound 7 which carries a Tyr-D-Ala-Gly-Phe opioid message sequence showed good opioid affinity (1 nM at both delta and mu opioid receptors) and bioactivity (34.9 nM in MVD and 42 nM in GPI/LMMP bioassays).


Subject(s)
Fentanyl/analogs & derivatives , Fentanyl/pharmacology , Narcotics/chemical synthesis , Narcotics/pharmacology , Animals , Fentanyl/chemical synthesis , Fentanyl/chemistry , Humans , Inhibitory Concentration 50 , Molecular Structure , Narcotics/chemistry , Picolines , Rats , Receptors, Opioid, delta/metabolism , Receptors, Opioid, mu/metabolism , Structure-Activity Relationship
14.
J Med Chem ; 49(6): 1946-52, 2006 Mar 23.
Article in English | MEDLINE | ID: mdl-16539382

ABSTRACT

A series of cyclic lactam analogues of gamma-MSH (H-Tyr1-Val2-Met3-Gly4-His5-Phe6-Arg7-Trp8-Asp9-Arg10-Phe11-Gly12-OH) with a bulky hydrophobic residue in the direct proximity to the pharmacophore (Xaa-D-Phe/D-Nal(2')-Arg-Trp) were designed and synthesized by solid-phase methods. A variety of amino acids with a broad range of hydrophobic/hydrophilic properties was introduced in position 5 to further explore their complementary role in receptor selectivity. Biological evaluation of these peptides revealed several analogues with potent hMC3R agonist and hMC3R/hMC5R antagonist activities, and good receptor selectivity. Analogue 4, c[Nle-Arg-D-Phe-Arg-Trp-Glu]-NH2, was found to be a very potent and selective hMC3R agonist (EC50=1.2 nM, 112% act). In addition, analogue 13, c[Nle-Val-D-Nal(2')-Arg-Trp-Glu]-NH2, was identified as an hMC3R/hMC5R antagonist with the best selectivity against the hMC4R in this series (pA2(hMC3R)=8.4; pA2(hMC5R)=8.7). These results indicate the significance of steric factors in melanocortin receptor selectivity and suggest that introduction of bulky residues in the direct proximity to the melanocortin pharmacophore is an effective approach to design of novel hMC3R and hMC5R selective ligands.


Subject(s)
Lactams/chemical synthesis , Peptides, Cyclic/chemical synthesis , Receptor, Melanocortin, Type 3/agonists , Receptor, Melanocortin, Type 3/antagonists & inhibitors , Receptors, Corticotropin/antagonists & inhibitors , gamma-MSH/chemistry , Adenylyl Cyclases/biosynthesis , Binding, Competitive , Cell Line , Drug Design , Humans , Hydrophobic and Hydrophilic Interactions , Lactams/chemistry , Lactams/pharmacology , Models, Molecular , Peptides, Cyclic/chemistry , Peptides, Cyclic/pharmacology , Radioligand Assay , Receptor, Melanocortin, Type 3/chemistry , Receptors, Corticotropin/chemistry , Receptors, Melanocortin , Structure-Activity Relationship
15.
Acta Crystallogr Sect E Struct Rep Online ; 62(7): o2815-o2816, 2006 Jul.
Article in English | MEDLINE | ID: mdl-17268579

ABSTRACT

The structure of the title compound, a fentanyl derivative with formula C(36)H(36)N(3)O(3) (+)·Cl(-)·2CH(3)OH, crystallizes as a racemic mixture. The organic cation has an extended conformation and the structure displays O-H⋯O, O-H⋯Cl and N-H⋯Cl hydrogen bonding.

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