piperidines and plerixafor

Asthma is a chronic inflammatory respiratory disease accompanied with airway inflammation, airway remodeling and bronchial hyperresponsiveness. Chemokines are important for the recruitment of immune cells to the lung, which play an important role in the formation and development of asthma. Targeting the chemokine receptors to anti-inflammation and anti-asthma is a new strategy and some candidate drugs are discovered recently. This review is focused on the development of chemokine receptor antagonists for anti-asthma, which will promote the compound designations.

Topics: Animals; Anti-Asthmatic Agents; Asthma; Benzylamines; Cyclams; Heterocyclic Compounds; Humans; Phenylurea Compounds; Piperidines; Pyridazines; Receptors, CCR1; Receptors, CCR3; Receptors, CCR4; Receptors, Chemokine; Receptors, CXCR4

The activation of the G-protein coupled receptor CXCR4 by its ligand CXCL12α is involved in a large variety of physiological and pathological processes, including the growth of B cells precursors and of motor axons, autoimmune diseases, stem cell migration, inflammation, and several neurodegenerative conditions. Recently, we demonstrated that CXCL12α potently stimulates the functional recovery of damaged neuromuscular junctions via interaction with CXCR4. This result prompted us to test the neuroregeneration activity of small molecules acting as CXCR4 agonists, endowed with better pharmacokinetics with respect to the natural ligand. We focused on NUCC-390, recently shown to activate CXCR4 in a cellular system. We designed a novel and convenient chemical synthesis of NUCC-390, which is reported here. NUCC-390 was tested for its capability to induce the regeneration of motor axon terminals completely degenerated by the presynaptic neurotoxin α-Latrotoxin. NUCC-390 was found to strongly promote the functional recovery of the neuromuscular junction, as assayed by electrophysiology and imaging. This action is CXCR4 dependent, as it is completely prevented by AMD3100, a well-characterized CXCR4 antagonist. These data make NUCC-390 a strong candidate to be tested in human therapy to promote nerve recovery of function after different forms of neurodegeneration.

Topics: Animals; Benzylamines; Cyclams; Heterocyclic Compounds; Indazoles; Mice; Mice, Inbred Strains; Motor Neurons; Nerve Degeneration; Nerve Regeneration; Neuromuscular Junction; Piperidines; Presynaptic Terminals; Primary Cell Culture; Pyridines; Rats; Receptors, CXCR4; Spider Venoms

To test whether the signaling axis CXCL12α-CXCR4 is activated upon crush/cut of the sciatic nerve and to test the activity of NUCC-390, a new CXCR4 agonist, in promoting nerve recovery from damage.. The sciatic nerve was either crushed or cut. Expression and localization of CXCL12α and CXCR4 were evaluated by imaging with specific antibodies. Their functional involvement in nerve regeneration was determined by antibody-neutralization of CXCL12α, and by the CXCR4 specific antagonist AMD3100, using as quantitative read-out the compound muscle action potential (CMAP). NUCC-390 activity on nerve regeneration was determined by imaging and CMAP recordings.. CXCR4 is expressed at the injury site within the axonal compartment, whilst its ligand CXCL12α is expressed in Schwann cells. The CXCL12α-CXCR4 axis is involved in the recovery of neurotransmission of the injured nerve. More importantly, the small molecule NUCC-390 is a strong promoter of the functional and anatomical recovery of the nerve, by acting very similarly to CXCL12α. This pharmacological action is due to the capability of NUCC-390 to foster elongation of motor neuron axons both in vitro and in vivo.. Imaging and electrophysiological data provide novel and compelling evidence that the CXCL12α-CXCR4 axis is involved in sciatic nerve repair after crush/cut. This makes NUCC-390 a strong candidate molecule to stimulate nerve repair by promoting axonal elongation. We propose this molecule to be tested in other models of neuronal damage, to lay the basis for clinical trials on the efficacy of NUCC-390 in peripheral nerve repair in humans.

Topics: Animals; Axons; Benzylamines; Chemokine CXCL12; Cyclams; Disease Models, Animal; Heterocyclic Compounds; Indazoles; Mice; Mice, Inbred C57BL; Nerve Regeneration; Piperidines; Pyridines; Receptors, CXCR4; Schwann Cells; Sciatic Nerve; Sciatic Neuropathy

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzylamines; Chemokine CXCL12; Class I Phosphatidylinositol 3-Kinases; Cyclams; Gene Expression Regulation, Neoplastic; Genetic Heterogeneity; Heterocyclic Compounds; Humans; Immunoglobulin Heavy Chains; Integrin alpha4; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; Natalizumab; Piperidines; Prognosis; Protein-Tyrosine Kinases; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, CXCR4; Signal Transduction; Survival Analysis

[D-Lys3]-GHRP-6 is regarded as a highly selective growth-hormone secretagogue receptor (GHSR) antagonist and has been widely used to investigate the dependency of GHSR-1a signalling mediated by acylated ghrelin. However, [D-Lys3]-GHRP-6 has been reported to influence other cellular processes which are unrelated to GHSR-1a. This study aimed to examine the effects of [D-Lys3]-GHRP-6 on autophagic and apoptotic cellular signalling in skeletal muscle. [D-Lys3]-GHRP-6 enhanced the autophagic signalling demonstrated by the increases in protein abundances of beclin-1 and LC3 II-to-LC3 1 ratio in both normal muscle and doxorubicin-injured muscle. [D-Lys3]-GHRP-6 reduced the activation of muscle apoptosis induced by doxorubicin. No histological abnormalities were observed in the [D-Lys3]-GHRP-6-treated muscle. Intriguingly, the doxorubicin-induced increase in centronucleated muscle fibres was not observed in muscle treated with [D-Lys3]-GHRP-6, suggesting the myoprotective effects of [D-Lys3]-GHRP-6 against doxorubicin injury. The [D-Lys3]-GHRP-6-induced activation of autophagy was found to be abolished by the co-treatment of CXCR4 antagonist, suggesting that the pro-autophagic effects of [D-Lys3]-GHRP-6 might be mediated through CXCR4. In conclusion, [D-Lys3]-GHRP-6 exhibits pro-autophagic effects on skeletal muscle under both normal and doxorubicin-injured conditions.

Topics: Amides; Animals; Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Beclin-1; Benzylamines; Cyclams; Doxorubicin; Heterocyclic Compounds; Male; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins; Muscle Cells; Muscle, Skeletal; Oligopeptides; Piperidines; Quaternary Ammonium Compounds; Quinazolinones; Receptors, CXCR4; Signal Transduction

The failure of standard treatment for patients diagnosed with glioblastoma (GBM) coupled with the highly vascularized nature of this solid tumor has led to the consideration of agents targeting VEGF or VEGFRs, as alternative therapeutic strategies for this disease. Despite modest achievements in survival obtained with such treatments, failure to maintain an enduring survival benefit and more invasive relapsing tumors are evident. Our study suggests a potential mechanism by which anti-VEGF/VEGFR therapies regulate the enhanced invasive phenotype through a pathway that involves TGFβR and CXCR4. VEGFR signaling inhibitors (Cediranib and Vandetanib) elevated the expression of CXCR4 in VEGFR-expressing GBM cell lines and tumors, and enhanced the in vitro migration of these lines toward CXCL12. The combination of VEGFR inhibitor and CXCR4 antagonist provided a greater survival benefit to tumor-bearing animals. The upregulation of CXCR4 by VEGFR inhibitors was dependent on TGFβ/TGFβR, but not HGF/MET, signaling activity, suggesting a mechanism of crosstalk among VEGF/VEGFR, TGFβ/TGFβR, and CXCL12/CXCR4 pathways in the malignant phenotype of recurrent tumors after anti-VEGF/VEGFR therapies. Thus, the combination of VEGFR, CXCR4, and TGFβR inhibitors could provide an alternative strategy to halt GBM progression.

Topics: Adult; Aged; Angiogenesis Inhibitors; Animals; Benzylamines; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Cyclams; Female; Glioblastoma; Heterocyclic Compounds; Humans; Interleukin-2 Receptor alpha Subunit; Male; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Middle Aged; Neoplasm Invasiveness; Piperidines; Protein Kinase Inhibitors; Quinazolines; Receptor Cross-Talk; Receptors, CXCR4; Receptors, Transforming Growth Factor beta; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Time Factors; Up-Regulation; Xenograft Model Antitumor Assays

Chemotherapeutic agents produce dose-limiting peripheral neuropathy through mechanisms that remain poorly understood. We previously showed that AM1710, a cannabilactone CB₂ agonist, produces antinociception without producing central nervous system (CNS)-associated side effects. The present study was conducted to examine the antinociceptive effect of AM1710 in rodent models of neuropathic pain evoked by diverse chemotherapeutic agents (cisplatin and paclitaxel). A secondary objective was to investigate the potential contribution of alpha-chemokine receptor (CXCR4) signaling to both chemotherapy-induced neuropathy and CB₂ agonist efficacy.. AM1710 (0.1, 1 or 5 mg/kg i.p.) suppressed the maintenance of mechanical and cold allodynia in the cisplatin and paclitaxel models. Anti-allodynic effects of AM1710 were blocked by the CB₂ antagonist AM630 (3 mg/kg i.p.), but not the CB1 antagonist AM251 (3 mg/kg i.p.), consistent with a CB₂-mediated effect. By contrast, blockade of CXCR4 signaling with its receptor antagonist AMD3100 (10 mg/kg i.p.) failed to attenuate mechanical or cold hypersensitivity induced by either cisplatin or paclitaxel. Moreover, blockade of CXCR4 signaling failed to alter the anti-allodynic effects of AM1710 in the paclitaxel model, further suggesting distinct mechanisms of action.. Our results indicate that activation of cannabinoid CB₂ receptors by AM1710 suppresses both mechanical and cold allodynia in two distinct models of chemotherapy-induced neuropathic pain. By contrast, CXCR4 signaling does not contribute to the maintenance of chemotherapy-induced established neuropathy or efficacy of AM1710. Our studies suggest that CB₂ receptors represent a promising therapeutic target for the treatment of toxic neuropathies produced by cisplatin and paclitaxel chemotherapeutic agents.

Topics: Animals; Benzylamines; Chromones; Cisplatin; Cryopyrin-Associated Periodic Syndromes; Cyclams; Disease Models, Animal; Heterocyclic Compounds; Hyperalgesia; Indoles; Male; Paclitaxel; Peripheral Nervous System Diseases; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB2; Receptors, CXCR4; Signal Transduction; Time Factors; Treatment Outcome

CCR5 and CXCR4 are the two main coreceptors essential for HIV entry. Therefore, these chemokine receptors have become important targets in the search for anti-HIV agents. Here, we describe the establishment of a novel CD4+ cell line, U87.CD4.CCR5.CXCR4, stably expressing both CCR5 and CXCR4 at the cell surface.. In these cells, intracellular calcium signalling through both receptors can be measured in a single experiment upon the sequential addition of CXCR4- and CCR5-directed chemokines. The U87.CD4.CCR5.CXCR4 cell line reliably supported HIV-1 infection of diverse laboratory-adapted strains and primary isolates with varying coreceptor usage (R5, X4 and R5/X4) and allows to investigate the antiviral efficacy of combined CCR5 and CXCR4 blockade. The antiviral effects recorded in these cells with the CCR5 antagonist SCH-C and the CXCR4 antagonist AMD3100 were similar to those noted in the single CCR5- or CXCR4-transfected U87.CD4 cells. Furthermore, the combination of both inhibitors blocked the infection of all evaluated HIV-1 strains and isolates.. Thus, the U87.CD4.CCR5.CXCR4 cell line should be useful in the evaluation of CCR5 and CXCR4 antagonists with therapeutic potential and combinations thereof.

Topics: Anti-HIV Agents; Benzylamines; Calcium Signaling; CCR5 Receptor Antagonists; CD4-Positive T-Lymphocytes; Cell Line; Cell Line, Tumor; Chemokines; Cyclams; Cyclic N-Oxides; Heterocyclic Compounds; Humans; Jurkat Cells; Oximes; Piperidines; Pyridines; Receptors, CCR5; Receptors, CXCR4