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   Biotech / MedicalIndications -- obesity/erectile dysfunction


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From: scaram(o)uche8/11/2017 12:30:20 PM
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J Med Chem. 2017 Aug 9. doi: 10.1021/acs.jmedchem.7b00707. [Epub ahead of print]

Novel Diarylurea Based Allosteric Modulators of the Cannabinoid CB1 Receptor: Evaluation of Importance of 6-Pyrrolidinylpyridinyl Substitution.

Nguyen T, German N, Decker AM, Langston TL, Gamage TF, Farquhar CE, Li JX, Wiley JL, Thomas BF, Zhang Y.

Allosteric modulators of the cannabinoid CB1 receptor have recently been reported as an alternative approach to modulate the CB1 receptor for therapeutic benefits. In this study, we report the design and synthesis of a series of diarylureas derived from PSNCBAM-1 (2). Similar to 2, these diarylureas dose-dependently inhibited CP55,940-induced intracellular calcium mobilization and [35S]GTP-?-S binding while enhancing [3H]CP55,940 binding to the CB1 receptor. Structure-activity relationship studies revealed that the pyridinyl ring of 2 could be replaced by other aromatic rings and the pyrrolidinyl ring is not required for CB1 allosteric modulation. 34 (RTICBM-74) had similar potencies as 2 in all in vitro assays but showed significantly improved metabolic stability to rat liver microsomes. More importantly, 34 was more effective than 2 in attenuating the reinstatement of extinguished cocaine-seeking behavior in rats, demonstrating the potential of this diarylurea series as promising candidates for the development of relapse treatment of cocaine addiction.

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From: scaram(o)uche8/18/2017 4:59:00 PM
   of 435
 
Oxid Med Cell Longev. 2017;2017:2186383. doi: 10.1155/2017/2186383. Epub 2017 Jul 26.

Activation of Endocannabinoid Receptor 2 as a Mechanism of Propofol Pretreatment-Induced Cardioprotection against Ischemia-Reperfusion Injury in Rats.

Sun HJ1, Lu Y2, Wang HW1, Zhang H3, Wang SR4, Xu WY1, Fu HL1, Yao XY5, Yang F6, Yuan HB1.

1
Department of Anesthesiology, Changzheng Hospital Affiliated to Second Military Medical University, No. 415 Fengyang Road, Shanghai 200003, China.
2
Department of Neurology, PLA Rocket Force General Hospital, No. 16 Xinjiekouwai Street, Beijing 100088, China.
3
Department of Anesthesiology, PLA Rocket Force General Hospital, No. 16 Xinjiekouwai Street, Beijing 100088, China.
4
Nursing School of Shanghai Jiguang Polytechnic College, No. 2859 Shuichan Road, Shanghai 201901, China.
5
Hebei North University School of Medicine, Zhangjiakou, Hebei 075000, China.
6
School of Pharmacy, Second Military Medical University, No. 325 Guohe Road, Shanghai 200433, China.

Propofol pretreatment before reperfusion, or propofol conditioning, has been shown to be cardioprotective, while its mechanism is unclear. The current study investigated the roles of endocannabinoid signaling in propofol cardioprotection in an in vivo model of myocardial ischemia/reperfusion (I/R) injury and in in vitro primary cardiomyocyte hypoxia/reoxygenation (H/R) injury. The results showed that propofol conditioning increased both serum and cell culture media concentrations of endocannabinoids including anandamide (AEA) and 2-arachidonoylglycerol (2-AG) detected by LC-MS/MS. The reductions of myocardial infarct size in vivo and cardiomyocyte apoptosis and death in vitro were accompanied with attenuations of oxidative injuries manifested as decreased reactive oxygen species (ROS), malonaldehyde (MDA), and MPO (myeloperoxidase) and increased superoxide dismutase (SOD) production. These effects were mimicked by either URB597, a selective endocannabinoids degradation inhibitor, or VDM11, a selective endocannabinoids reuptake inhibitor. In vivo study further validated that the cardioprotective and antioxidative effects of propofol were reversed by selective CB2 receptor antagonist AM630 but not CB1 receptor antagonist AM251. We concluded that enhancing endogenous endocannabinoid release and subsequent activation of CB2 receptor signaling represent a major mechanism whereby propofol conditioning confers antioxidative and cardioprotective effects against myocardial I/R injury.

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From: scaram(o)uche8/18/2017 5:31:08 PM
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Br J Pharmacol. 2017 Aug 14. doi: 10.1111/bph.13980. [Epub ahead of print]

Suppression of acute and anticipatory nausea by peripherally restricted FAAH inhibitor in animal models: Role of PPARa and CB1 receptors.

Rock EM1, Moreno-Sanz G, Limebeer CL1, Petrie GN1, Angelini R2, Piomelli D2, Parker LA1.

1
Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON, N1G 2W1.
2
Department of Anatomy and Neurobiology, University of California, Irvine, 92697-4621.

To evaluate the ability of the peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor, URB937 (cyclohexylcarbamic acid 3'-carbamoyl-6-hydroxybiphenyl-3-yl ester) to suppress acute and anticipatory nausea in rats, and to examine the pharmacological mechanism of such an effect.
EXPERIMENTAL APPROACH:
We investigated the potential of URB937 to reduce the establishment of lithium chloride (LiCl)-induced conditioned gaping (a model of acute nausea) and to reduce the expression of contextually elicited conditioned gaping (a model of anticipatory nausea) in rats. As well, the role of CB1 receptors, CB2 receptors and the peroxisome proliferator-activated receptor-a (PPARa) in the anti-nausea effect of URB937 was examined. The potential of URB937 to suppress FAAH activity in tissue collected from the area postrema (AP), prefrontal cortex (PFC), liver and duodenum, and to elevate levels of FAAH substrates - anandamide (AEA), N-oleoylethanolamide (OEA) and N-palmitoylethanolamide (PEA) - in the AP was also evaluated.
KEY RESULTS:
URB937 (1 and 3 mg/kg, i.p.) reduced acute nausea by a PPARa mechanism and reduced anticipatory nausea (3 mg/kg, ip) by a CB1 mechanism. The PPARa agonist, GW7647, similarly attenuated acute nausea. URB937 reduced FAAH activity in the liver and the duodenum, but not in the PFC. In addition, URB937 reduced FAAH activity and elevated levels of fatty-acid ethanolamides (FAEs) in the AP, a brain region that is not protected by the blood-brain barrier.
CONCLUSIONS AND IMPLICATIONS:
The anti-nausea action of URB937 may occur in the AP, and may involve PPARa to suppress acute nausea and CB1 to suppress anticipatory nausea.

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From: scaram(o)uche8/21/2017 3:08:41 PM
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Review of various commercial development efforts, packed with surface info. Good starting point.

Love to see the totality of data behind this..... "The cell-based ligand screening involved approximately 80 phytocannabinoids, with the initial screen resulting in the identification of several hits that were effective in preventing the activation of the cells by transforming growth factor-beta, or TGF-beta."

bioworld.com

Something like this pops out, and you wonder if cognitive disorder is just a shot in the dark or ????. In context, one might go.... "yeah, neuropathic pain, but.... huh?" Different context?

"Cleveland Clinic spinout Neurotherapia Inc. is seeking to move NTRX-07, a CB2 agonist, into the clinic to treat cognitive disorder and neuropathic pain"

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From: scaram(o)uche8/23/2017 2:13:51 PM
   of 435
 
Biol Psychiatry. 2017 Jul 8. pii: S0006-3223(17)31761-4. doi: 10.1016/j.biopsych.2017.06.032. [Epub ahead of print]

Positive Allosteric Modulation of Cannabinoid Receptor Type 1 Suppresses Pathological Pain Without Producing Tolerance or Dependence.

Slivicki RA1, Xu Z2, Kulkarni PM3, Pertwee RG4, Mackie K5, Thakur GA3, Hohmann AG6.

1
Program in Neuroscience, Indiana University, Bloomington, Indiana; Psychological and Brain Sciences, Indiana University, Bloomington, Indiana.
2
Psychological and Brain Sciences, Indiana University, Bloomington, Indiana.
3
Department of Pharmaceutical Sciences, Center for Drug Discovery, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts.
4
Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland, United Kingdom.
5
Program in Neuroscience, Indiana University, Bloomington, Indiana; Psychological and Brain Sciences, Indiana University, Bloomington, Indiana; Gill Center for Biomolecular Science, Bloomington, Indiana.
6
Program in Neuroscience, Indiana University, Bloomington, Indiana; Psychological and Brain Sciences, Indiana University, Bloomington, Indiana; Gill Center for Biomolecular Science, Bloomington, Indiana. Electronic address: hohmanna@indiana.edu.

BACKGROUND:
Activation of cannabinoid CB1 receptors suppresses pathological pain but also produces unwanted central side effects. We hypothesized that a positive allosteric modulator of CB1 signaling would suppress inflammatory and neuropathic pain without producing cannabimimetic effects or physical dependence. We also asked whether a CB1 positive allosteric modulator would synergize with inhibitors of endocannabinoid deactivation and/or an orthosteric cannabinoid agonist.
METHODS:
GAT211, a novel CB1 positive allosteric modulator, was evaluated for antinociceptive efficacy and tolerance in models of neuropathic and/or inflammatory pain. Cardinal signs of direct CB1-receptor activation were evaluated together with the propensity to induce reward or aversion and physical dependence. Comparisons were made with inhibitors of endocannabinoid deactivation (JZL184, URB597) or an orthosteric cannabinoid agonist (WIN55,212-2). All studies used 4 to 11 subjects per group.
RESULTS:
GAT211 suppressed allodynia induced by complete Freund's adjuvant and the chemotherapeutic agent paclitaxel in wild-type but not CB1 knockout mice. GAT211 did not impede paclitaxel-induced tumor cell line toxicity. GAT211 did not produce cardinal signs of direct CB1-receptor activation in the presence or absence of pathological pain. GAT211 produced synergistic antiallodynic effects with fatty acid amide hydrolase and monoacylglycerol lipase inhibitors in paclitaxel-treated mice. Therapeutic efficacy was preserved over 19 days of chronic dosing with GAT211, but it was not preserved with the monoacylglycerol lipase inhibitor JZL184. The CB1 antagonist rimonabant precipitated withdrawal in mice treated chronically with WIN55,212-2 but not in mice treated with GAT211. GAT211 did not induce conditioned place preference or aversion.
CONCLUSIONS:
Positive allosteric modulation of CB1-receptor signaling shows promise as a safe and effective analgesic strategy that lacks tolerance, dependence, and abuse liability.

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From: scaram(o)uche8/28/2017 3:33:29 PM
   of 435
 
Sci Rep. 2017 Aug 25;7(1):9560. doi: 10.1038/s41598-017-09808-8.

Pepcan-12 (RVD-hemopressin) is a CB2 receptor positive allosteric modulator constitutively secreted by adrenals and in liver upon tissue damage.

Petrucci V1,2, Chicca A1, Glasmacher S1, Paloczi J3, Cao Z3, Pacher P3, Gertsch J4.

1
Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, 3012, Bern, Switzerland.
2
Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
3
Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA.
4
Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, 3012, Bern, Switzerland. gertsch@ibmm.unibe.ch.

Pepcan-12 (RVD-hemopressin; RVDPVNFKLLSH) is the major peptide of a family of endogenous peptide endocannabinoids (pepcans) shown to act as negative allosteric modulators (NAM) of cannabinoid CB1 receptors. Noradrenergic neurons have been identified to be a specific site of pepcan production. However, it remains unknown whether pepcans occur in the periphery and interact with peripheral CB2 cannabinoid receptors. Here, it is shown that pepcan-12 acts as a potent (K i value ~50?nM) hCB2 receptor positive allosteric modulator (PAM). It significantly potentiated the effects of CB2 receptor agonists, including the endocannabinoid 2-arachidonoyl glycerol (2-AG), for [35S]GTP?S binding and cAMP inhibition (5-10 fold). In mice, the putative precursor pepcan-23 (SALSDLHAHKLRVDPVNFKLLSH) was identified with pepcan-12 in brain, liver and kidney. Pepcan-12 was increased upon endotoxemia and ischemia reperfusion damage where CB2 receptors play a protective role. The adrenals are a major endocrine site of production/secretion of constitutive pepcan-12, as shown by its marked loss after adrenalectomy. However, upon I/R damage pepcan-12 was strongly increased in the liver (from ~100 pmol/g to ~500 pmol/g) independent of adrenals. The wide occurrence of this endogenous hormone-like CB2 receptor PAM, with unforeseen opposite allosteric effects on cannabinoid receptors, suggests its potential role in peripheral pathophysiological processes

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From: scaram(o)uche12/23/2017 3:23:22 PM
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J Neurosci. 2017 Nov 22. pii: 1945-17. doi: 10.1523/JNEUROSCI.1945-17.2017. [Epub ahead of print]
Acetaminophen Relieves Inflammatory Pain Through CB1 Cannabinoid Receptors in the Rostral Ventromedial Medulla.
Klinger-Gratz PP1, Ralvenius WT1, Neumann E1, Kato A2, Nyilas R2, Lele Z2, Katona I2, Zeilhofer HU3,4.
Author information
1Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH-8057, Switzerland.2Institute of Experimental Medicine, Hungarian Academy of Sciences, 43 Szigony Street, H-1083 Budapest, Hungary.3Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH-8057, Switzerland zeilhofer@pharma.uzh.ch.4Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Vladimir-Prelog-Weg 1-5/10, CH-8093 Zürich, Switzerland.

Abstract
Acetaminophen (paracetamol) is a widely used analgesic and antipyretic drug with only incompletely understood mechanisms of action. Previous work, using models of acute nociceptive pain, indicated that analgesia by acetaminophen involves an indirect activation of CB1receptors by the acetaminophen metabolite and endocannabinoid re-uptake inhibitor AM 404. However, the contribution of the cannabinoid system to anti-hyperalgesia against inflammatory pain, the main indication of acetaminophen, and the precise site of the relevant CB1receptors have remained elusive. Here, we analyzed acetaminophen analgesia in mice of either sex with inflammatory pain and found that acetaminophen exerted a dose-dependent anti-hyperalgesic action, which was mimicked by intrathecally injected AM 404. Both compounds lost their anti-hyperalgesic activity in CB1-/- mice confirming the involvement of the cannabinoid system. Consistent with a mechanism down-stream of pro-inflammatory prostaglandin formation, acetaminophen also reversed hyperalgesia induced by intrathecal prostaglandin E2(PGE2). To distinguish between a peripheral/spinal and a supraspinal action, we administered acetaminophen and AM 404 to hoxB8-CB1-/-mice, which lack CB1 receptors from the peripheral nervous system and the spinal cord. These mice exhibited unchanged anti-hyperalgesia indicating a supraspinal site of action. Accordingly, local injection of the CB1 receptor antagonist rimonabant into the rostral ventromedial medulla (RVM) blocked acetaminophen-induced anti-hyperalgesia, while local RVM injection of AM 404 reduced hyperalgesia in wild-type mice but not in CB1-/- mice. Our results indicate that the cannabinoid system contributes not only to acetaminophen analgesia against acute pain but also against inflammatory pain, and suggest that the relevant CB1 receptors reside in the RVM.SIGNIFICANCE STATEMENT Acetaminophen is a widely used analgesic drug with multiple but only incompletely understood mechanisms of action including a facilitation of endogenous cannabinoid signaling via one of its metabolites. Our present data indicate that enhanced cannabinoid signaling is also responsible for the analgesic effects of acetaminophen against inflammatory pain. Local injections of the acetaminophen metabolite AM 404 and of cannabinoid receptor antagonists as well as data from tissue specific CB1 receptor deficient mice suggest the rostral ventromedial medulla as an important site of the cannabinoid-mediated analgesia by acetaminophen.

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From: scaram(o)uche12/23/2017 3:25:14 PM
   of 435
 
J Pharmacol Exp Ther. 2017 Nov 29. pii: jpet.117.245522. doi: 10.1124/jpet.117.245522. [Epub ahead of print]
Selective cannabinoid 2 receptor stimulation reduces tubular epithelial cell damage following renal ischemia-reperfusion injury.
Pressly JD1, Mustafa SM1, Abidi A1, Alghamdi S1, Pandey P2, Roy KK2, Doerksen R2, Moore BM1, Park F3.
Author information
1university of Tennessee health science center.2University of Mississippi.3University of Tennessee Health Sciences Center fpark@uthsc.edu bmoore@uthsc.edu.

Abstract
Ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI), which is an increasing problem in the clinic and has been associated with increased rates of mortality. Currently, therapies to treat AKI are not available, so identification of new targets which, upon diagnosis of AKI, can be modulated to ameliorate renal damage is essential. In this study, a novel cannabinoid receptor 2 (CB2) agonist, SMM-295, was designed, synthesized, and tested in vitro and in silico. In vivo testing of the CB2 agonist was performed using a mouse model of bilateral IRI, which is a common model to mimic human AKI. Molecular docking of SMM-295 into a CB2 active-state homology model showed that SMM-295 interacts well with key amino acids to stabilize the active-state. In HEK-293 cells, SMM-295 was capable of reducing cAMP production with a 66-fold selectivity for the CB2 versus the cannabinoid receptor 1 (CB1), and dose-dependently increased MAPK and Akt phosphorylation. In mice, SMM-295 was immediately administered upon reperfusion of the kidneys following the ischemia episode. Histological damage assessment 48 hours after reperfusion demonstrated reduced tubular damage in the presence of SMM-295. This was consistent with the reduced plasma markers of renal dysfunction, i.e., creatinine and NGAL, in SMM-295 treated mice. Mechanistically, kidneys treated with SMM-295 were shown to have elevated activation of Akt with reduced TUNEL-positive cells compared to vehicle-treated kidney following IRI. These data suggests that selective CB2 receptor activation could be a potential therapeutic target in the treatment for AKI.

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To: scaram(o)uche who wrote (349)12/28/2017 12:21:46 PM
From: scaram(o)uche
   of 435
 
From William Gerber, and the answer to his question is "no". But it was relatively simple to predict. One of biotech's sad stories, from over-zealous, greedy management.....

pbs.twimg.com

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From: scaram(o)uche12/31/2017 12:30:54 PM
   of 435
 
Life Sci. 2017 Dec 27. pii: S0024-3205(17)30677-X. doi: 10.1016/j.lfs.2017.12.030. [Epub ahead of print]

Surprising outcomes in cannabinoid CB1/CB2 receptor double knockout mice in two models of ischemia.

Ward SJ1, Castelli F2, Reichenbach ZW3, Tuma RF3.

1
Lewis Katz School of Medicine at Temple University, United States. Electronic address: saraward@temple.edu.
2
Novartis, Switzerland.
3
Lewis Katz School of Medicine at Temple University, United States.

AIMS:
We tested the hypothesis that CB1/CB2 receptor double knockout would produce significant increases in infarct size and volume and significant worsening in clinical score, using two mouse models, one of permanent ischemia and one of ischemia/reperfusion.

MAIN METHODS:
Focal cerebral infarcts were created using either photo induced permanent injury or transient middle cerebral artery occlusion. Infarct volume and motor function were evaluated in cannabinoid receptor 1/cannabinoid receptor 2 double knockout mice.

KEY FINDINGS:
The results surprisingly revealed that CB1/CB2 double knockout mice showed improved outcomes, with the most improvements in the mouse model of permanent ischemia.

SIGNIFICANCE:
Although the number of individuals suffering from stroke in the United States and worldwide will continue to grow, therapeutic intervention for treatment following stroke remains frustratingly limited. Both the cannabinoid 1 receptor (CB1R) and the cannabinoid 2 receptor (CB2R) have been studied in relationship to stroke. Deletion of the CB2R has been shown to worsen outcome, while selective CB2R agonists have been demonstrated to be neuroprotective following stroke. Although initial studies of CB1R knockout mice demonstrated increased injury following stroke, indicating that activation of the CB1R was neuroprotective, later studies of selective antagonists of the CB1R also demonstrated a protective effect. Surprisingly the double knockout animals had improved outcome. Since the phenotype of the double knockout is not dramatically changed, significant changes in the contribution of other homeostatic pathways in compensation for the loss of these two important receptors may explain these apparently contradictory results.

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