Blog

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are protein channels found in the plasma membranes of heart and brain cells that regulate neuronal excitability. HCN is well-known and used for the contribution of its pacemaker function to cardiac rhythm. In addition, several studies have linked the activities of HCN channels to both epilepsy and pain.

A recent study at the Icahn School of Medicine contends HCN channels to have substantial potential as a target for major depressive disorder therapeutics. Several animal models of depression have been able to demonstrate that ionic mechanisms play a key role in neuronal homeostasis and dysregulation. Because HCN channels are confirmed to regulate neuronal excitability, they may also have a role in mediating depression-related excitability.

A recent study by Tae, et al using transgenic mice showed that gabapentin impacted several HCN4 channels and had only a slight effect on HCN1 channels. Currently, there are very few drugs known to effect individual HCN channels. Therefore, gabapentin may be useful in studying the function of HCN4 specifically.

G0106 Gabapentin

Related Product Categories:

Analgesics and Antinociceptives

Antidepressants

Antiepileptics and Anticonvulsants

Sedatives and Hypnotics

References:

Ku SM, Han MH. HCN channel targets for novel antidepressant treatment. Neurotherapeutics. 2017 Jul;14(3):698-715. doi: 10.1007/s13311-017-0538-7.

Tae HS, Smith KM, Phillips AM, et al. Gabapentin modulates HCN4 channel voltage-dependence. Front Pharmacol. 2017 Aug 21;8:554. doi: 10.3389/fphar.2017.00554.

The endocannabinoid system is a set of proteins and endogenous ligands that regulates a variety of biological processes. It consists of cannabinoid receptors 1 (CB1) and 2 (CB2), the natural ligands 2-arachidonyl glycerol (2-AG) and N-arachidonylethanolamide (AEA or Anandamide), as well as proteins responsible for the hydrolysis of these ligands, such as monoacyl glycerol lipase (MAGL), fatty acid amide hydrolase (FAAH) and alpha/beta hydrolase domain 6 (ABHD6). CB1 is located mainly in brain tissues, while CB2 is found in the periphery. Endocannabinoid modulation is a research topic in neuroscience, immunology, cancer and obesity research.

Cannabinoid receptors 1 and 2 are G-protein coupled receptors (GPCRs). The results of activation/inhibition of CB1 and CB2 are still being explored.

CB Mixed Agonists

Besides endogenous ligands 2-AG and AEA, many synthetic endocannabinoids have been discovered. Mixed agonists (which interact with both CB1 and CB2) include WIN 55,212-2 and CP 55,940. Both of these agonist are able stimulate cannabinoid signaling, with no preference between the two receptors. Stimulation of CB1 and CB2 has been tied to analgesia, anti-diabetic, anti-obesity and anti-inflammation.

W317520 WIN 55212-2

C600000 CP 55,940

Selective CB antagonists

Antagonism of the cannabinoid receptors is under study for decreasing CB signaling. CB antagonists have been used in neuroscience, cancer and immunology research. AM251, a selective CB1 inverse agonist demonstrated benefits in an anti-obesity system. AM630, a selective CB2 inverse agonist, activates TRPA1 in sensory neurons.

CB1 Antagonists/Inverse Agonists

A480000 AM251

R3449 Rimonabant

CB2 Antagonists/Inverse Agonists

A480010 AM630

S680000 SR144528

J766160 JTE907

CB2 Agonists

CB2 selective agonists are ubiquitous throughout current academic literature. Synthetic CB2 agonists have been used to study the role of endocannabinoids in neurodegenerative disorders, diabetes, obesity and cancer. Agonists of the CB2 receptor have especially shown benefits as analgesic and anti-allodynic compounds.

L000033 L-759,633

H800010 HU308

J889290 JWH 133

J889280 JWH 015

G880000 GW 405833

A480020 AM1241

S182680 SER601

M184770 4-O-methylhonokiol

FAAH Inhibitors

Fatty acid amide hydrolase (FAAH) is responsible for the hydrolysis of AEA to arachidonic acid. Inhibition of FAAH results in an increase in AEA, which can stimulate CB1 and CB2 and activate down stream signaling pathways. FAAH inhibition is under investigation for pain attenuation and the reduction of neuro-inflammation. FAAH inhibitor URB597 demonstrates analgesic effects in mice. Inhibitor PF-3845 also reduces pain in mice stimulated with LPS, and reduces inflammation in mice models for traumatic brain injury.

U682040 URB597

P200000 PF-3845

MAGL Inhibitors

Monoacylglycerol lipase (MAGL) is responsible for the hydrolysis of 2-AG to arachidonic acid. Increasing the amount of 2-AG stimulates cannabinoid signaling. Inhibition of MAGL increases 2-AG, showing the benefits of increased 2-AG. JZL 184, an inhibitor of MAGL decreases pain in multiple mouse models, showing anti-nociceptive and reducing pain-related to cancer drugs in mice. URB602, another inhibitor of MAGL, also demonstrates anti-nociceptive properties.

J974440 JZL 184

U682042 URB602

ABHD6 Inhibitors

Alpha/Beta hydrolase domain 6 (ABHD6) also hydrolyzes 2-AG to arachidonic acid. The ABHD inhibitor WWL70 reduces weight gain in diet-induced obese mice. It also has anti-inflammatory properties by reducing the amount of pro-inflammatory prostaglandin expression.

W894440 WWL70

References:

Aquirre-Rueda D, Guerra-Ojeda S, Aldasoro M et al. WIN 55,212-2, agonist of cannabinoid receptors, prevents amyloid beta1-42 effects on astrocytes in primary culture. PLoS One. 2015 Apr 13;10(4):e0122843. PMID: 25874692

Hamamoto DT, Giridharagopalan S, and Simone DA. Acute and chronic administration of the cannabinoid receptor agonist CP 55,940 attenuates tumor-evoked hyperalgesia. Eur J Pharamacol. 2007 Mar 8;558(1-3): 73-87. PMID: 17250825.

Patil M, Patwardhan A, Salas MM, et al. Cannabinoid receptor antagonists AM251 and AM630 activate TRPA1 in sensory neurons. Neuropharmacology, 2011. Sep;61(4):778-88. PMID: 21645531.

Jenkin KA, O’Keefe L, Simcocks AC, et al. Chronic administration of AM251 improves albuminuria and renal tubular structure in obese rats. J Endocrin. 2015 May;225(2)113-24. PMID: 25804605.

Negrete R, Hervera A, Leazez S et al. The antinociceptive effects of JWH-015 in chronic inflammatory pain are produced by nitric oxide-cGMP-PKG-KATP pathway activation mediated by opioids. PLoS One. 2011;6(10):e26688. PMID: 22031841.

Ibrahim MM, Deng H, Zvonok A et al. Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS. Proc Natl Acad Sci USA. 2003 Sep 2;100(18):10529-33. PMID: 12917492.

Kwilasz AJ, Abdullah RA, Poklis JL et al. Effects of the fatty acid amide hydrolase inhibitor URB597 on pain-stimulated and pain-depressed behavior in rats. Behav Pharmacol. 2014 Apr;25(2):119-29. PMID: 24583930

Booker L, Kinsey SG, Abdullah RA et al. The fatty acid hydrolase (FAAH) inhibitor PF-3845 acts in the nervous system to reverse LPS-induced tactile allodynia in mice. Br J Pharmacol. 2012 Apr;165(8):2485-96. PMID: 21506952.

Comelli F, Giagnoni G, Bettoni I et al. The inhibition of monoacylglycerol lipase by URB602 showed an anti-inflammatory and anti-nociceptive effect in a murine model of acute inflammation. Br J Pharmacol. 2007 Nov;152(5):787-94. PMID:17700715.

Woodhams SG, Wong A, Barrett DA et al. Spinal administration of the monoacylglycerol lipase inhibitor JZL 184 produces robust inhibitory effects on nociceptive processing and the development of central sensitization in the rat. Br J Pharmacol. 2012 Dec;167(8):1609-19. PMID: 22924700.

Tanaka M, Moran S, Wen J et al. WWL70 attenuates PGE₂ production derived from 2-arachidonoylglycerol in microglia by ABHD6-independent mechanism. J Neuroinflammation. 2017 Jan 10;14(1):7. PMID: 28086912.

Cyclin-dependent kinases (CDKs) are an enzyme family that control cellular proliferation and growth. The interaction of CDKs with D-type cyclins results in the inactivation of retinoblastoma (Rb) tumor suppressor protein. Inhibiting the CDKs therefore allows the tumor suppressor to remain active.

Abemaciclib has previously demonstrated antitumor activity in HR+/HER2 metastatic breast cancer, renal cell carcinoma and several other solid tumor types. It’s been found to selectively inhibit CDK4 and CDK6. A recent study by Kosovec et al, further tests the potential of abemaciclib, this time for the treatment of esophageal adenocarcinoma (EAC).

The study evaluated several cell lines, monitoring apoptosis, proliferation, and pathway regulation during treatment with abemaciclib. Additionally, animals were induced to develop EAC and then treated with abemaciclib by intraperitoneal injection. The study was quite successful, the treated animals showed decreased tumor volumes and decreased prevalence of the disease altogether, while the treated cell lines showed increased apoptosis and decreased proliferation.

Overactive CDKs or inactive Rb protein are a common thread among several different cancer types, which makes CDK an interesting target of investigation for cancer treatments.

A044176 Abemaciclib

Full List of CDK Inhibitors

Reference:

Kosovec JE, Zaidi AH, Omstead NA, et al. CDK4/6 dual inhibitor abemaciclib demonstrates compelling preclinical activity against esophageal adenocarcinoma: a novel therapeutic option for a deadly disease. Oncotarget. 2017 Nov 1;8(59):100421-100432. doi: 10.18632/oncotarget.22244.

The Karyopherin superfamily consists of seven known proteins that mediate the majority of transport of molecules through the nuclear pores in a cell nucleus.

One of these proteins: chromosome region maintenance1 (CRM1, aka XPO1 or exportin1) is a key transporter protein that exports cargo from within the cell nucleus out to the cytoplasm. The role of CRM1 is to export tumor suppressor proteins and growth regulatory proteins.

Over-expression of CRM1 has been found in various malignancies and leads to mislocalization of several growth and survival factors. Inhibiting CRM1 leads to an accumulation of tumor suppressor proteins, which eventually triggers apoptosis, killing off the problem causing cell. CRM1 also plays an important role in viral replication. Preventing this protein, which the virus is dependent on for survival, to function should then prevent the virus from replicating, effectively shutting it down.

Lab studies have found that the CRM1 inhibitor KPT-276 shows activity against several types of cancer, including glioblastoma, lung cancer, and breast cancer, among others.

Studies on the CRM1 inhibitor verdinexor have shown that these inhibitors also act as antiviral agents. Both in vitro and in vivo studies have demonstrated the antiviral benefit of a treatment based on CRM1 inhibition, particularly in the face of the drug resistance that has developed against common antiviral drugs.

The CRM1 inhibitors KPT-276 and Verdinexor are now available from LKT Laboratories for further research use.

References

Mathew C, Ghildyal R. CRM1 inhibitors for antiviral therapy. Front Microbiol. 2017;8:1171. doi: 10.3389/fmicb.2017.01171.

Cheng Y, Holloway MP, Nguyen K, et al. XPO1 (CRM1) inhibition represses STAT3 activation to drive a survivin-dependent oncogenic switch in triple-negative breast cancer. Mol Cancer Ther. 2014 Mar; 13(3):675-686. doi: 10.1158/1535-7163.MCT-13-0416.

Wang S, Han X, Wang J, et al. Antitumor effects of a novel chromosome region maintenance 1 (CRM1) inhibitor on non-small cell lung cancer cells in vitro and in mouse tumor xenografts. PLoS One. 2014 Mar 4;9(3):e89848. doi: 10.1371/journal.pone.0089848

Green Al, Ramkissoon SH, McCauley D, et al. Preclinical antitumor efficacy of selective exportin 1 inhibitors in glioblastoma. Neuro Oncol. 2015 May;17(5):697-707. doi: 10.1093/neuonc/nou303.

Lundberg L, Pinkham C, de la Fuente C, et al. Selective inhibitor of nuclear export (SINE) compounds alter new world alphavirus capsid localization and reduce viral replication in mammalian cells. PLoS Negl Trop Dis. 2016 Nov 30;10(11):e0005122. doi: 10.1371/journal.pntd.0005122.

Perwitasari O, Johnson S, Yan X, et al. Antiviral efficacy of verdinexor in vivo in two animal models of influenza A virus infection. PLoS One. 2016 Nov 28;11(11):e0167221. doi: 10.1371/journal.pone.0167221.

Incidence of diabetes has been growing worldwide over the last 20 years. Due to its impact on health worldwide, a search for novel treatment options for diabetes has been undertaken. Two promising compounds for the treatment of type 2 diabetes mellitus are linagliptin and empagliflozin.

Linagliptin is an inhibitor of dipeptidyl peptidase-4 (DPP-4). DPP-4 is expressed in a wide variety of cells, and performs various functions in these cells. In diabetes, inhibition of DPP-4 leads to an increase of insulin and lowering of blood glucose. Linagliptin is efficacious in rodent models mimicking type 1 diabetes. Linagliptin reduces oxidative stress to levels of normal rats, lessens incidence of cardiac injury. Additionally, linagliptin reduces renal injury and ameliorates kidney fibrosis in the same streptozotocin-induced type 1 diabetes rodent model.

Empagliflozin is an inhibitor of sodium glucose cotransporter type 2 (SGLT-2). Empagliflozin lowers the amount of blood glucose and increases the amount of insulin found in Zucker diabetic fatty rats. It also reduces cardiovascular stress in type 2 diabetes mice models with prolonged treatment.

Combined treatment with lingaliptin/empagliflozin in human subjects showed modest weight loss, and no incidents of hypoglycemia.

Linagliptin and Empagliflozin are now available from LKT Laboratories, Inc. for your research needs.

L337521 Linagliptin

E499601 Empagliflozin

References:

Hansen HH, Jelsing J, Hansen CF et al. The Sodium Glucose Cotransporter Type 2 Inhibitor Empagliflozin Preserves Beta-Cell Mass and Restores Glucose Homeostasis in the Male Zucker Diabetic Fatty Rat. J Pharmacol Exp Ther. September 2014. 350:657-664. doi: 10.1124/jpet/114/213454.

Kanasaki K, Shi S, Kanasaki M et al. Lingaliptin-Mediated DPP-4 Inhibitions Ameliorates Kidney Fibrosis in Streptozotocin-Induced Diabetic Mice by Inhibiting Endothelial-to-Mesenchymal Transition in a Therapeutic Regimen. Diabetes. June 2014. 63:2120-2131. doi: 10.2337/db13-1029.

Lin B, Koibuchi, N, Hasegawa, Y et al. Glycemic control with empagliflozin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injursy and cognitive dysfunction in obese and type 2 diabetic mice. Cardiovascular Diabetology, 2014, 13:148. doi: 10.1186/s12933-014-0148-1.

Salheen SM, Panchapakesan U, Pollock CA and Woodman OL. The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Preserves Endothelial Function in Mesenteric Arteries from Type 1 Diabetic Rats withouth Decreasing Plasma Glucose. PLoS ONE 10(11): e0143941. doi: 10.10371/journal.pone/0143941.

Woo, V. Empagliflozin/linagliptin single-tablet combination: first-in-class treatment option. Int J Clin Pract, Dec 2015, 69, 12, 1427-1437. doi: 10.1111/ijcp.12720.

LKT Labs continues to expand its catalog with six new compounds for the new year… the first of many additions in store for 2018!

P327211 Pifithrin-α Hydrobromide: Inhibitor of p53 that may also inhibit other signaling pathways including heat shock and glucocorticoid.

P327212 Pifithrin-α-cyclic Hydrobromide: A more stable and less cytotoxic analog of pifithrin-alpha.

B030966 BAY 11-7082: Potential inhibitor of NF-kB, and many components of inflammatory signaling pathways including PI3K/Akt/IKK/NFkB, ERK/JNK/AP-1, TBK1/IRF-3, and Jak-2/STAT-1.

R183731 Resiquimod: An imidazoquinoline compound that is a TLR7/8 agonist.

L337521 Linagliptin: A dipeptidyl peptidase 4 inhibitor glucose-lowering compound with low risk of inducing hypoglycaemia.

E499601 Empagliflozin: A sodium glucose cotransporter 2 inhibitor found to ameliorate glucose intolerance and insulin resistance.

Leucine-rich repeat kinase 2 (LRRK2) is an important target in the treatment of Parkinson’s disease (PD). In addition to being over-expressed in neurons, LRRK2 mutations are found in patients with late-onset PD, and believed to be a common cause. One such mutation related to onset of PD is Glutamine 2019 to serine. This mutation increases the kinase activity of LRRK2, which in turn increases neurodegeneration.

Knockdown of LRRK2 has been shown to modify synaptogenesis, resulting in mutated synapses compared to normal mice neurons. But, knockdown of LRRK2 in rats also resulted in loss of neuroinflammation due to reduced expression of a-synuclein. This expression was demonstrated in LRRK2 knockout mice in vivo.

Inhibiting LRRK2 activity with small molecules is a potential target for the treatment of PD. The inhibitor PF-06447475 is a small molecule inhibitor that inhibits LRRK2 kinase activity. PF-06447475 acts in both wild type and G2019S mutated LRRK2. It inhibits neurodegeneration caused by the overexpression of a-synuclein PF-06447475 also demonstrates an ability to cross the blood-brain barrier. It is well tolerated, with rats showing no toxicities after 4 weeks dosing in animal trials.

LRRK2 inhibitors available from LKT Laboratories include:

P2100 PF-06447475

C9808 CZC-54252

G5216 GNE-7915

References:

Parisiadou, L., Yu, J. Sgobio C. et al. “LRRK2 regulates synaptogenesis and dopamine receptor activation through modulation of PKA activity” Nat. Neurosci. 2014 March; 17(3): 367-376. Doi: 10.1038/nn.3636.

Daher, J.P.L., Volpicelli-Daley, L.A., Blackburn, J.P., et al. “Abrogation of alpha-synuclein-mediated dopaminergic neurodegeneration in LRRK2-deficiaent rats” Proc. Nat. Acad. Sci. 2014, June. 111(25): 9289-9294. Doi: 10.1073/pnas.1403215111.

Daher, J.P.L., Abdelmotilib, H.A., Hu, X., et al. “Leucine-rich Repeat Kinase 2 (LRRK2) Pharmacological Inhibition Abates alpha-Synuclein Gene-induced Neurodegeneration” J. Biol. Chem. 2015 August. 290(32): 19433-19444. Doi: 10.1074/jbc.M115.660001.

Nemorosone is a polycyclic polyprenylated acylphloroglucinol derived from beeswax and bee saliva. Closely related to hyperforin, nemorosone shows activity as an anti-cancer and anti-inflammatory compound.

Nemorosone inhibited growth of xenografts of MIA-PaCA-2 pancreatic cancer cells in mice over a 28-day trial period. Nemorosone showed better activity than standard treatment with gemcitabine in the same model. Additionally, nemorosone does not activate CYP3A4, unlike structurally related molecule hyperforin. Nemorosone, therefore, has a longer half-life and better absorption in biological systems.

Nemorosone is available exclusively from LKT Laboratories, Inc.

N176498 Nemorosone

H9863 Hyperforin Dicyclohexylammonium

G1745 Gemcitabine Hydrochloride

Reference:

Wolf, RJ, Hilger RA, Hoheisel JD, et al. (2013) “In Vivo Activity and Pharmacokinetics of Nemorosone on Pancreatic Cancer Xenografts.” PLoS ONE 8(9): e74555. Doi:10.1371/journal.pone.0074555

Right now there are millions of people worldwide who are suffering from Alzheimer’s disease. Alzheimer’s is the most common form of dementia, but it is actually not a normal part of aging. The underlying cause is not yet understood and there is no cure, although there are medications that may help to improve some of the symptoms of the disease.

There are currently several medications to enhance cognition available for people suffering from Alzheimer’s disease. Comparison of the safety and effectiveness of the four FDA-approved drugs: donepezil, rivastigmine, galantamine, and memantine, ranked donepezil as most effective. Donepezil has proven to be effective in moderate to severe Alzheimer’s, however, in mild cases it did not improve cognition but rather produced several adverse side effects.

A new study with grey mouse lemurs shows that sleep-induced memory impairment was reversed by acute administration of donepezel and memantine in both young and aged animals. This study gave similar results as observed with monkeys and with humans, but contrasted with the observations from studies that had used rodents. Mouse lemur is one of the smallest primates in the world. Because the lemur is a primate, it has a closer phylogenetic proximity to humans, and may therefore be a better model for drug development, and particularly for research on aging.

Perhaps research using lemurs or other primates rather than rodents may prove to be a more powerful comparison tool and help to get to the bottom of this disease.

D5753 Donepezil Hydrochloride

G0246 Galantamine Hydrobromide

M1749 Memantine

R3586 Rivastigmine Tartrate

All Alzheimer’s Related Chemicals

Nauert, Rick. Study finds donepezil best Alzheimer’s drug for improving cognition. Psych Central. 2 Oct. 2017.  Accessed 19 Oct 2017.

Rahman A, Lamberty Y, Schenker E, et al. Effects of acute administration of donepezil or memantine on sleep-deprivation-induced spatial memory deficit in young and aged non-human primate grey mouse lemurs (Microcebus murinus). PLoS One. 2017 Sep 18;12(9):e0184822 DOI: 10.1371/journal.pone.0184822

PAC-1 (Procaspase activating compound 1) is an anti-cancer compound that works against a multitude of cancer types. PAC-1 works by binding zinc ions that inactivate the activity of procaspase-3.

Procaspase-3 is the zymogen form of caspase-3. High expression of procaspase-3 is found in a variety of cancer types including brain, breast, lung and colon cancers. Because of its high expression in some rare carcinoma, procaspase-3 is an excellent anti-cancer target. Caspase-3 is needed for cells to undergo apoptosis, or programmed cell-death. Procaspase-3 is activated to caspase-3 by caspase-8 or caspase-9, after the apoptosis signaling cascade is begun.

One atom that inhibits the activation of procaspase-3 to caspase-3 is endogenous zinc found in cells. PAC-1 selectively chelates to zinc ions bound to procaspase-3. With PAC-1 chelating to zinc ions, pro-caspase-3 is activated to caspase-3 and cancerous cells can undergo apoptosis. PAC-1 has recently been used in a phase I clinical trial for efficacy against glioblastoma. PAC-1 is an attractive molecule against this cancer type due to its ability to cross the blood-brain barrier in the body.

PAC-1 also acts synergistically with some common cancer treatments. It has been shown that PAC-1 can act synergistically with doxorubicin, both in vitro and in vivo. Experiments in canines showed that both canine lymphoma and canine osteosarcoma tumors regressed with combined doxorubicin/PAC-1 treatment.

PAC-1 is available now from LKT Laboratories, Inc.

P004080 PAC-1

References:

1. Putt, K.S., Chen, G.W., Pearson, J. M. et al. “Small-molecule activation of procaspase-3 to caspase-3 as a personalized anticancer strategy.” Nature Chem. Biol. 2006 Oct; 2(10): 543-550. Doi:10.1038/nchembio814.

2. Botham, R. C., Roth, H. S., Book, A.P. et al. “Small-Molecule Procaspase-3 Activation Sensitizes Cancer to Treatment with Diverse Chemotherapeutics.” ACS Cent. Sci. 2016 Aug 24; 2(8):545-59. Doi: 10.1021/acscentsci.6b00165.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are protein channels found in the plasma membranes of heart and brain cells that regulate neuronal excitability. HCN is well-known and used for the contribution of its pacemaker function to cardiac rhythm. In addition, several studies have linked the activities of HCN channels to both epilepsy and pain.

A recent study at the Icahn School of Medicine found HCN channels to have substantial potential as a target for major depressive disorder therapeutics. Several animal models of depression have been able to demonstrate that ionic mechanisms play a key role in neuronal homeostasis and dysregulation. Because HCN channels are confirmed to regulate neuronal excitability, they may also have a role in mediating depression-related excitability.

A recent study by Tae, et al using transgenic mice showed that gabapentin impacted several HCN4 channels and had only a slight effect on HCN1 channels. Currently, there are very few drugs known to effect individual HCN channels. Therefore, gabapentin may be useful in studying the function of HCN4 specifically.

G0106 Gabapentin

Related Categories:

Analgesics and Antinociceptives

Antidepressants

Antiepileptics and Anticonvulsants

Sedatives and Hypnotics

References:

Ku SM, Han MH. HCN channel targets for novel antidepressant treatment. Neurotherapeutics. 2017 Jul;14(3):698-715. doi: 10.1007/s13311-017-0538-7.

Tae HS, Smith KM, Phillips AM, et al. Gabapentin modulates HCN4 channel voltage-dependence. Front Pharmacol. 2017 Aug 21;8:554. doi: 10.3389/fphar.2017.00554.

Peptides and proteins as therapeutics have the advantage over other drugs of using a wide variety of targets with high specificity while having low levels of toxicity. Oftentimes the peptide or protein may be further modified chemically to improve its effectiveness in a biological system. In order to track useful and non-useful modifications and the plethora of peptides and proteins that have been studied, a new database of all FDA approved protein and peptide therapeutics has been collected into one place: THPdb.

One peptide drug already present in the THPdb database is oxytocin, also known as pitocin. Oxytocin is a peptide produced by the pituitary gland that acts as both a hormone and as a neurotransmitter in your brain. It is also prepared synthetically and used by medical doctors to induce labor. Oxytocin also regulates behavior in several ways, including maternal nurturing, control of anxiety, social recognition and attachment, and increasing trust. In addition, oxytocin receptor abnormalities have been linked to autism spectrum disorders, and oxytocin administration to some mouse autism spectrum disorder models was shown to improve behavior. In a recent study Ripamonti, et al, investigated the influence of oxytocin on brain development of fetal and early postnatal mice. They found that lack of oxytocin in these early stages led to autism spectrum disorder-like symptoms.

Cherepanov, et al, recently created modified versions of oxytocin, in the form of three versions of lipid conjugates, in an attempt to increase half-life to provide long-lasting effects and to improve transport across the blood-brain barrier. They were able to find one modification that did result in longer-lasting activity than the original oxytocin and may hold potential for further therapeutic development. With future progress of the THPdb database, useful modifications like these that help with common problems such as crossing the blood-brain barrier may be easier to track. Sorting and finding effective modifications in an efficient way would be a great help in developing new innovative peptide and protein therapies.

LKT Labs has a wide selection of peptide compounds, including oxytocin and many more. In addition to our catalog peptides, we can also provide custom peptide sequences synthesized to your needs.

O9497 Oxytocin

A4849 Amyloid-beta

E5240 Leu-Enkephalin

V0275 [Arg8]-Vasotocin

Z6269 Z-Pro-D-Leu

Usmani SS, Bedi G, Samuel JS, et al. THPdb: Database of FDA-approved peptide and protein therapeutics. PLoS One. 2017 Jul 31;12(7):e0181748. PMID: 28759605. Doi: 10.1371/journal.pone.0181748.

Ripamonti S, Ambrozkiewicz MC, Guzzi F, et al. Transient oxytocin signaling primes the development and function of excitatory hippocampal neurons. Elife. 2017 Feb 23;6.pii:e22466. PMID: 28231043. Doi: 10.7554/eLife.22466.

Cherepanov SM, Yokoyama S, Mizuno A, et al. Structure-specific effects of lipidated oxytocin analogs on intracellular calcium levels, parental behavior, and oxytocin concentrations in the plasma and cerebrospinal fluid in mice. Pharmacol Res Perspect. 2017 Jan 17;5(1):e00290. PMID: 28596839. Doi: 10.1002/prp2.290.

Theaflavin is a polyphenol found in black tea, along with related compounds theaflavin-3-gallate and Theaflavin-3,3’-digallate. Black tea, one of the most common beverages consumed worldwide, is made from the fermentation of green tea leaves. During this process, green tea polyphenols are modified into the theaflavins. These naturally occurring compounds demonstrate beneficial effects in a variety of diseases.

Recent studies have found that theaflavins reduce cell proliferation and induce apoptosis of ovarian cancer cells. These compounds also work against a cisplatin resistant ovarian cancer cell line A2780/CP70. Further studies with theaflavin-3, 3’-digallate showed that cells were arrested in the G2 stage of the cell cycle.

Additionally, theaflavins can act as anti-inflammatory compounds. When used in the LPS model for inflammation, theaflavin-3,3’-digallate decreased expression of cytokine inflammation markers TNFa, IL-1b, and IL-6. This occurred in both an in vitro and in vivo system, while showing very little cytotoxic effects.

An antimicrobial mechanism is postulated for Theaflavins. A recent manuscript shows that all of the theaflavins can inhibit 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR), a key enzyme in bacterial terpenoid biosynthesis, in an uncompetitive manner.

The Theaflavin family of molecules is available from LKT Laboratories, Inc.

T286161 Theaflavin

T286165 Theaflavin-3-gallate

T286163 Theaflavin-3, 3’-digallate

References:

1. Gao Y., Rankin GO., Tu, Y., and Chen YC., “Inhibitory Effects of the Four Main Theaflavin Derivatives Found in Black Tea on Ovarian Cancer Cells.” Anticancer Res. 2016 Feb;36(2):643-51.

2. Tu Y., Kim E., Gao Y., et al. “Theaflavin-3,3’-digallate induces apoptosis and G2 cell cycle arrest through the Akt/MDM2/p53 pathway in cisplatin-resistant ovarian cancer A2780/CP70 cells.” Int. J. Oncol. 2016 Jun;48(6):2657-65. Doi: 10.3892/ijo.2016.3472.

3. Wu Y., Jin F., Wang Y., et al. “In vitro and in vivo anti-inflammatory effects of theaflavin-3,3’-digallate on lipopolysaccharide-induced inflammation.” Eur. J. Pharmacol. 2017 Jan 5;794:52-60. Doi:10.1016/j.ejphar.2016.11.027

4. Hui X., Yue, Q., Zhang DD., et al. “Antimicrobial mechanism of theaflavins: They target 1-deoxy-D-xylulose 5-phosphate reductoisomerase, the key enzyme of the MEP terpenoid biosynthetic pathway.” Sci Rep. 2016 Dec 12;6:38945. Doi: 10.1038/srep38945.

Sponges are known to produce secondary metabolites that act as chemical defense mechanisms. Because the sponge is a sessile organism with a fragile body, it has limited capability to defend itself otherwise. The sponge’s secondary metabolites act as chemical weapons and can ward off dangers such as attacking predators or bacterial infections. One of these secondary metabolites, produced by sponges belonging to the order Verongida, is the compound Aeroplysinin.

Aeroplysinin has been studied in several biological systems in the lab for its potential use against human diseases. Recently, Park, et al has done studies that indicate aeroplysinin attenuates the Wnt/b-catenin signaling in DLD-1 colon cancer cells. b-Catenin is involved in the development and progression of colon cancer, and so it may make a useful target on which to focus therapeutics or chemopreventive agents. Experimental treatment of HEK293 cells with aeroplysinin decreased the amount of intracellular b-catenin, meaning that aeroplysinin may make a useful chemopreventive agent and should be further investigated for this use.

In addition to showing inhibition of colon cancer, other studies have found aeroplysinin to demonstrate antibiotic, antimicrobial, antiviral, anti-inflammatory, and anti-angiogenic activities.

There are thousands of species of marine sponges alive today and each produces a unique set of secondary metabolites necessary for its own survival. Each of these secondary metabolites is a compound with some bioactivity that may provide a useful starting point for developing new compounds to battle human diseases.

Several compounds found in marine sponges are available from LKT Labs including:

A1865 Aeroplysinin

G0244 alpha-Galactosylceramide

M0255 Manzamine A

P8382 Puupehenone

V3212 Vidarabine

V3213 Vidarabine Monophosphate

Garcia-Vilas JA, Martinez-Poveda B, Quesada AR, Medina MA. Aeroplysinin-1, a sponge-derived multi-targeted bioactive marine drug. Mar Drugs. 2015 Dec 22;14(1):1. Doi: 10.3390/md14010001

Park S, Kim JH, Kim JE, et al. Cytotoxic activity of aeroplysinin-1 against colon cancer cells by promoting b-catenin degradation. Food Chem Toxicol. 2016 Jul;93:66-72. Doi: 10.1016/j.fct.2016.04.019

The NOTCH signaling pathway is involved in cell proliferation, differentiation and cell cycle progression. Four membrane-bound NOTCH receptors are found in mammals (NOTCH1, NOTCH2, NOTCH3 and NOTCH4), which interact with 5 different extracellular ligands (Jagged 1, jagged 2, delta like ligand 1, 3 and 4). Ligands bind NOTCH on the extracellular domain, starting the NOTCH signaling cascade, eventually resulting in release of the NOTCH intracellular domain (NICD). The NICD then translocates to the nucleus, effecting the activation of various genes, such as hairy/enhancer of split (HES).

γ-secretase is responsible for cleavage of the NOTCH intracellular domain from the transmembrane portion of the protein. Inhibitors of γ-secretase (GSIs) therefore are useful as inhibitors of the NOTCH signaling cascade. NOTCH signaling inhibitors have been extensively studied in hematological malignancies, as well as other cancerous tissues. LKT Laboratories offers a variety of γ-secretase inhibitors.

MK-0752 (3-[4-(4-chlorophenyl) sulfonyl-4-(2,5-difluorophenyl) cyclohexyl] propanoic acid) was also submitted for phase I clinical trials. Results of this test show that MK-0752 was tolerated by patients with advanced solid tumors, and showed efficacy as an anti-cancer agent.

DAPT (N-[N-(3,5- Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester) was found to inhibit the proliferation of ovarian cancer cells, as well as inducing apoptosis of these cells. DAPT also inhibits proliferation of gastric carcinmoma cells.

These γ-secretase inhibitors and more are available from LKT Labs Inc.

F4432 FLI-06

D0260 DAPT

D1773 Deshydroxy LY-411575

M4200 MK-0752

References:

Yuan X., Wu H., et al. “Notch signaling: An emerging therapeutic target for cancer treatment” Cancer Letters 369, (2015) pp 20-27. Doi: 10.1016/j.canlet.2015.07.048

Yao, Y., Ni, Y. et al. “The role of Notch signaling in gastric carcinoma: molecular pathogenisis and novel therapeutic targets.” Oncotarget. (2017) May 11. Doi: 10.18632/oncotarget.17809.

Feng, Z., Xu, W. et al. “Inhibition of gamma-secretase in Notch1 signaling pathway as a novel treatment for ovarian cancer.” Oncotarget. (2017) Jan 31; 8(5):8283-8293. Doi:10.18632/oncotarget.14152.

Gu, Y., Masiero, M. and Banham AH. “Notch signaling: its roles and therapeutic potential in hematological malignancies.” Oncotarget. (2016) May 17;7(20):29804-23. Doi: 10.18632/oncotarget.7772.

Mycotoxins are toxic compounds that are sometimes found as contaminants in food due to molds. They can be transferred through the food chain and may appear as contaminants in fruits, grains, crops, and any food products produced from these items, such as juices or cereals. Mycotoxins have a negative impact on human health as they can be carcinogenic, neurotoxic, and toxic to the endocrine and immune systems.

In some cases it may be possible to decontaminate food where mycotoxins are present. However, there are various restrictions worldwide on what processes may be used and there are limitations to the effectiveness of these methods. New decontamination methods, such as the exposure to cold atmospheric pressure plasma, are currently under development.

Due to personal choice and cultural differences in preferences of food, it is also difficult to set a safe and acceptable level of allowable contamination in the first place. Typically, the mycotoxins found with the lowest levels of acceptability set by many authorities are aflatoxins and ochratoxin, with limits in the single ppb range. However, each country sets its own limits.

Alternatively, Osteresch et al promote the idea of each individual’s exposure being assessed through a physiological sampling. They have recently developed a method to test dried blood spots or dried serum spots for 27 different mycotoxins in a single analysis. Samples can easily be collected by a minimally invasive method, generally by heel, ear, or finger pricking followed by spotting onto a filter paper card. By using individual biomonitoring, better understanding of human health impacts can be gained in the long run.

The data produced by a human biomonitoring program can provide insights not only to our individual and collective exposure but also to how that exposure may change over time. In addition, the long-term effects of consistent low-level exposure can be reassessed alongside environmental datasets to give us better insights on the risks to human health of exposures to these compounds.

Many mycotoxins, including ochratoxin and several of the aflatoxins are available at LKT Labs to be used as reference standards.

Mycotoxins

O0829 Ochratoxin A

A2044 Aflatoxin B1

A2046 Aflatoxin B2

A2048 Aflatoxin G1

A2050 Aflatoxin G2

A2052 Aflatoxin M1

A2054 Aflatoxin M2

A2244 Aflatoxicol

Mycotoxin Decontamination of Food: Cold Atmospheric Pressure Plasma versus “Classic” Decontamination. Toxins (Basel). 2017 Apr 28;9(5). PMID: 28452957

Multi-mycotoxin analysis using dried blood spots and dried serum spots. Anal Bioanal Chem. 2017 May;409(13):3369-3382. PMID: 28299415

A recent study published in PLoS ONE shows that the naproxen analog ATB 346 has chemopreventative effects in a murine cancer model.

ATB 346 is a hydrogen sulfide (H2S) releasing analog of naproxen, a non-steroidal anti-inflammatory drug (NSAID). It acts by inhibiting cyclooxygenase, and decreasing endogenous PGE2. ATB 346 does not have the same GI damaging effect as naproxen, however. Previous studies have shown that in mice, treatment with ATB 346 reduced traumatic brain injury by reducing inflammation and suppressing neural cell death.

In a study by Paul-Clark et al., the effect of ATB 346 was measured in APCMin/+ mice, a model for gastro-intestinal cancer. Researchers found that treatment with ATB 346 reduced the size and formation of intestinal polyps, pre-malignant lesions that form in this model. ATB 346 decreased the formation in comparison to the parent compound naproxen as well. Continuous treatment with ATB 346 significantly reduced polyp formation. Fourteen days of treatment significantly decreased the polyp score for APCMin/+ mice. The effect of ATB 346 was seen starting treatment at both week 6 and week 12 of life for the mice. Additionally, ATB 346 reduced expression of cMYC and β-catenin, two major cancer biomarkers. In all, the study shows that ATB 346 works better than naproxen in this mouse model, and does not exhibit the same GI side effects that appear with naproxen treatment.

ATB 346, as well as naproxen, is available from LKT Labs.

A7604 ATB 346

N0061 D-Naproxen

N0062 D, L-Naproxen

Campolo M., Esposito E. et al. “Hydrogen sulfide-releasing cyclooxygenase inhibitor ATB-346 enhances motor function and reduces cortical lesion volume following traumatic brain injury in mice” Journal of Neuroinflammation. 2014, 11:196 DOI: 10.1186/s12974-014-0196-1

Paul-Clark, M., Elsheikh W. et al., “Profound Chemopreventative Effects of a Hydrogen Sulfide-Releasing NSAID in the APCMin/+ Mouse Model of Intestinal Tumorigenesis” PLoS ONE (2016), 11(2):e0147289. Doi:10.1371/journal.pone.0147289

4-O-Methylhonokiol (M184770) is isolated from the bark of Magnolia officinalis along with the natural products honokiol and magnolol. This lignan has found utility in a range of research fields, from neuroscience to cancer.

Researchers have found that 4-O-Methylhonokiol can act as a neuroprotective agent, potentially by acting as an acetylcholinesterase inhibitor in mice. In a Morris water maze assay, after scopoloamine treatment to induce memory impairment, mice that received 4-O-Methylhonokiol performed better with reduced escape latency time compared with control mice. This was found in conjunction with suppressed acetylcholinesterase activity in mouse hippocampus and cortex with 4-O-Methylhonokiol treatment.

A similar study showed that 4-O-Methylhonokiol decreases the effect of LPS (lipopolysaccharides)-induced memory impairment in mice. In a Morris water maze experiment, mice performed better after LPS injection when treated with 4-O-Methylhonokiol, compared to control. Further experiments showed that 4-O-Methylhonokiol does this by inhibiting NF-κB, which in turn decreased the expression of Aβ1-42 in mouse brains. Additionally, 4-O-Methylhonokiol reduced expression of nitric oxide and PGE2, which are over-expressed in LPS-treated mice models.

More neuroprotective studies of 4-O-Methylhonokiol have shown that it increases the amount of 2-arachidonyl glycerol in mice brain by activating cannabinoid type-2 receptor (CB2), and acting as a substrate-specific inhibitor of COX-2. The inhibtion of COX-2 was shown by a decrease in the presence of PGE2 in mouse brain. This dual activity could allow for beneficial effects in neuroinflammatory states with over-expressed CB2 and COX-2 proteins.

In addition to neuroprotective studies, 4-O-methylhonokiol also has activity as an anti-cancer compound, as well as other disease states. 4-O-Methylhonokiol (M184770) is now available from LKT Laboratories, Inc. in 5, 10, 25, and 100 mg size bottles.

M184770 4-O-Methylhonokiol

H5654 Honokiol

M0125 Magnolol

Lee, Y. K., Yuk, D. Y. et al. “Protective effect of the ethanol extract of Magnolia officinalis and 4-O-methylhonokiol on scopolamine-induced memory impairment and the inhibition of acetylchlinesterase activity” J Nat Med. 2009 Jul; 63(3):274-282 PMID: 19343477

Lee, Y.J., Choi, D.Y. et al. “Inhibitory effect of 4-O-methylhonokiol on lipopolysaccharide-induced neuroinflammation, amyloidogenesis and memory impairment via inhibition of nuclear factor-kappaB in vitro and in vivo models” J Neuroinflammation. 2012 Feb 19;9:35 PMID: 22339795

Chicca, A. Gachet, M.S. et al. “4’-O-methylhonokiol increases levels of 2-arachidonoyl glycerol in mouse brain via selective inhibition of its COX-2-mediated oxygenation” J Neuroinflammation. 2015 May 13; 12:89 PMID: 25962384

Type 2 diabetes is a chronic condition in which the body resists the effects of insulin or doesn’t produce enough insulin to maintain a healthy glucose level. Since insulin is a hormone that regulates the the metabolism of sugar, type 2 diabetes typically leads to high blood sugar, which can lead to heart disease or kidney failure.

Sulforaphane, a natural compound found in broccoli, cauliflower, and other cruciferous vegetables, has been identified as a possible counter to type 2 diabetes. In a study published in June of 2017 by Lund University, R-Sulforaphane from LKT Labs was shown to suppress glucose production from hepatic cells by nuclear translocation of NRF2, and decreased the expression of important enzymes in gluconeogenesis. Sulforaphane also reversed the disease signature in the livers of diabetic animals. Finally, sulforaphane was also administered to obese patients with dysregulated type 2 diabetes, and was shown to reduce fasting blood glucose and glycated hemoglobin.

R,S-Sulforaphane is a synthetic organosulfur compound that displays a variety of interesting characteristics, including anticancer, antimicrobial, antioxidative, anti-inflammatory, and neuroprotective activities. It is a phase II enzyme inducer and induces the expression of the transcription factor Nrf2.

R-Sulforaphane is found naturally in cruciferous vegetables such as broccoli, and has been continuously studied for its health benefits, sometimes showing increased effectiveness compared to its synthetic R,S counterpart in various models.

S8044 R,S-Sulforaphane, High Purity (≥99%)

S8047 R,S-Sulforaphane, Research Grade (≥97%)

S8046 R-Sulforaphane, High Purity (≥99%)

S8048 R-Sulforaphane, Research Grade (≥97%)

1. Axelsson AS, Tubbs E, Rosengren AH, et al. “Sulforaphane reduces hepatic glucose production and improves glucose control in patients with type 2 diabetes.“. Sci Transl Med. 2017 Jun 14;9(394).

Tauopathies are a group of neurodegenerative diseases characterized by misfolding and abnormal accumulation of tau protein in the brain leading to the formation of neurofibrillary tangles. Some of these diseases include Alzheimer’s, Amyotropic lateral sclerosis, Argyrophilic brain disease, Parkinson’s, post traumatic stress disorder, and traumatic brain injury, just to name a few.

Although neurofibrillary tangles are strongly correlated with neurodegeneration, they are so far only known to be a correlation, and may not necessarily a causative factor.

In a study by McCormick et al, published in Biological Psychiatry, 1120 drugs were screened for activity against tau neurotoxicity. The chosen drugs already had FDA approval for human use, but are meant for a variety of other therapeutic uses, unrelated to tau. The goal of this study was to search out a known drug that also happens to target the underlying neurodegenerative pathology of tauopathies.

Finding new uses for already known drugs accelerates the process of discovery and clinical testing because the safety and toxicity profiles are already known.

This drug screen found a positive hit with one compound in particular: azaperone. Azaperone has previously been used in animals as a tranquillizer and as an antipsychotic. This study used a cuticle defective mutant of C. elegans, a roundworm in which most neuronal proteins are similar to human, as the test model.

The animals treated with azaperone produced reduced levels of insoluble tau, compared with untreated animals. Treatment was also shown to prevent loss of motor neurons. The test was carried forward into human HEK293 cells and was found to produce a U-shaped dose response curve. Using either too high or too low concentration of azaperone, the insoluble tau level increased.

Repositioning of known drugs into new uses may prove to be an efficient way to develop new therapies. While the correct dosage for an alternate use may need to be determined, the drug toxicity is already proven to be acceptable.

Many compounds with known therapeutic and toxicity profiles, including azaperone and several additional antipsychotics, are available at LKT Labs.

A9801 Azaperone

Antipsychotics available at LKT Labs

McCormick AV, Wheeler JM, et al. Dopamine D2 receptor antagonism suppresses tau aggregation and neurotoxicity. Biol Psychiatry. 2013 Mar 1;73(5):464-471. PMID: 23140663.

Sengupta U, Portelius E, et al. Tau oligomers in cerebrospinal fluid in Alzheimer’s disease. Ann Clin Transl Neurol. 2017 Mar 14;4(4):226-235. PMID: 28382304.