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   Biotech / MedicalIndications -- obesity/erectile dysfunction


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From: scaram(o)uche7/17/2017 1:15:49 PM
1 Recommendation   of 435
 
Neuropharmacology. 2017 Jun 30. pii: S0028-3908(17)30305-2. doi: 10.1016/j.neuropharm.2017.06.032. [Epub ahead of print]

Inhibition of the endocannabinoid-regulating enzyme monoacylglycerol lipase elicits a CB1 receptor-mediated discriminative stimulus in mice.

Owens RA1, Mustafa MA1, Ignatowska-Jankowska BM1, Damaj MI2, Beardsley PM1, Wiley JL3, Niphakis MJ4, Cravatt BF4, Lichtman AH5.

1
Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA.
2
Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA; RTI International, 3040 Cornwallis Road, Research Triangle Park, NC, 27709-2194, USA; The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
3
RTI International, 3040 Cornwallis Road, Research Triangle Park, NC, 27709-2194, USA.
4
The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
5
Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA. Electronic address: aron.lichtman@vcuhealth.org.

Substantial challenges exist for investigating the cannabinoid receptor type 1 (CB1)-mediated discriminative stimulus effects of the endocannabinoids, 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (anandamide; AEA), compared with exogenous CB1 receptor agonists, such as ?9-tetrahydrocannabinol (THC) and the synthetic cannabinoid CP55,940. Specifically, each is rapidly degraded by the respective hydrolytic enzymes, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH). Whereas MAGL inhibitors partially substitute for THC and fully substitute for CP55,940, FAAH inhibitors do not substitute for either drug. Interestingly, combined FAAH-MAGL inhibition results in full THC substitution, and the dual FAAH-MAGL inhibitor SA-57 serves as its own discriminative training stimulus. Because MAGL inhibitors fully substitute for SA-57, we tested whether the selective MAGL inhibitor MJN110 would serve as a training stimulus. Twelve of 13 C57BL/6J mice learned to discriminate MJN110 from vehicle, and the CB1 receptor antagonist rimonabant dose-dependently blocked its discriminative stimulus. CP55,940, SA-57, and another MAGL inhibitor JZL184, fully substituted for MJN110. In contrast, the FAAH inhibitor PF-3845 failed to substitute for the MJN110 discriminative stimulus, but produced a 1.6 (1.1-2.2; 95% confidence interval) leftward shift in the MJN110 dose-response curve. Inhibitors of other relevant enzymes (i.e., ABHD6, COX-2) and nicotine did not engender substitution. Diazepam partially substituted for MJN110, but rimonabant failed to block this partial effect. These findings suggest that MAGL normally throttles 2-AG stimulation of CB1 receptors to a magnitude insufficient to produce cannabimimetic subjective effects. Accordingly, inhibitors of this enzyme may release this endogenous brake producing effects akin to those produced by exogenously administered cannabinoids.

J Pharmacol Exp Ther. 2017 Aug;362(2):296-305. doi: 10.1124/jpet.117.241901. Epub 2017 Jun 7.

Cannabinoid CB2 Agonist GW405833 Suppresses Inflammatory and Neuropathic Pain through a CB1 Mechanism that is Independent of CB2 Receptors in Mice.

Li AL1, Carey LM1, Mackie K1, Hohmann AG2.

1
Department of Psychological and Brain Sciences (A-L L, L.M.C., K.M., A.G.H.), Program in Neuroscience (L.M.C., K.M., A.G.H.), Gill Center for Biomolecular Science (K.M., A.G.H.), Indiana University, Bloomington, Indiana.
2
Department of Psychological and Brain Sciences (A-L L, L.M.C., K.M., A.G.H.), Program in Neuroscience (L.M.C., K.M., A.G.H.), Gill Center for Biomolecular Science (K.M., A.G.H.), Indiana University, Bloomington, Indiana hohmanna@indiana.edu.

GW405833, widely accepted as a cannabinoid receptor 2 (CB2) agonist, suppresses pathologic pain in preclinical models without the unwanted central side effects of cannabinoid receptor 1 (CB1) agonists; however, recent in vitro studies have suggested that GW405833 may also behave as a noncompetitive CB1 antagonist, suggesting that its pharmacology is more complex than initially appreciated. Here, we further investigated the pharmacologic specificity of in vivo antinociceptive actions of GW405833 in models of neuropathic (i.e., partial sciatic nerve ligation model) and inflammatory (i.e., complete Freund's adjuvant model) pain using CB2 and CB1 knockout (KO) mice, their respective wild-type (WT) mice, and both CB2 and CB1 antagonists. GW405833 (3, 10, and 30 mg/kg i.p.) dose dependently reversed established mechanical allodynia in both pain models in WT mice; however, the antiallodynic effects of GW405833 were fully preserved in CB2KO mice and absent in CB1KO mice. Furthermore, the antiallodynic efficacy of GW405833 (30 mg/kg i.p.) was completely blocked by the CB1 antagonist rimonabant (10 mg/kg i.p.) but not by the CB2 antagonist SR144528 (10 mg/kg i.p.). Thus, the antinociceptive properties of GW405833 are dependent on CB1 receptors. GW405833 (30 mg/kg i.p.) was also inactive in a tetrad of tests measuring cardinal signs of CB1 activation. Additionally, unlike rimonabant (10 mg/kg i.p.), GW405833 (10 mg/kg, i.p.) did not act as a CB1 antagonist in vivo to precipitate withdrawal in mice treated chronically with ?9-tetrahydrocannabinol. The present results suggest that the antiallodynic efficacy of GW405833 is CB1-dependent but does not seem to involve engagement of the CB1 receptor's orthosteric site.

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From: scaram(o)uche7/23/2017 4:33:15 PM
   of 435
 
(I most often skip posting new agonist or antagonist chemistries, as there is a constant stream of new ones. But the first abstract has the in vivo kicker. The second abstract describes an animal injury model, and some may want to stop reading short of it.)

J Med Chem. 2017 Jul 20. doi: 10.1021/acs.jmedchem.7b00724. [Epub ahead of print]

Amidoalkylindoles as Potent and Selective Cannabinoid Type 2 Receptor Agonists with In Vivo Efficacy in a Mouse Model of Multiple Sclerosis.

Shi Y, Duan YH, Ji YY, Wang ZL, Wu YR, Gunosewoyo H, Xie XY, Chen JZ, Yang F, Li J, Tang J, Xie X, Yu LF.

Selective CB2 agonists represent an attractive therapeutic strategy for the treatment of a variety of diseases without psychiatric side effects mediated by the CB1 receptor. We carried out a rational optimization of a black market designer drug SDB-001 that led to the identification of potent and selective CB2 agonists. A 7-methoxy or 7-methylthio substitution at the 3-amidoalkylindoles resulted in potent CB2 antagonists (27 or 28, IC50 = 16-28 nM). Replacement of the amidoalkyls from 3-position to the 2-position of the indole ring dramatically increased the agonist selectivity on the CB2 over CB1 receptor. Particularly, compound 57 displayed a potent agonist activity on the CB2 receptor (EC50 = 114-142 nM) without observable agonist or antagonist activity on the CB1 receptor. Furthermore, 57 significantly alleviated the clinical symptoms and protected the murine central nervous system from immune damage in an experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis.

Brain Res. 2017 Jul 14. pii: S0006-8993(17)30268-8. doi: 10.1016/j.brainres.2017.06.020. [Epub ahead of print]

The synthetic cannabinoid WIN55212-2 ameliorates traumatic spinal cord injury via inhibition of GAPDH/Siah1 in a CB2-receptor dependent manner.

Su BX1, Chen X2, Huo J1, Guo SY3, Ma R4, Liu YW5.

1
Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
2
Department of Anesthesiology, Shaanxi Provincial People's Hospital, Xi'an 710068, China.
3
Department of Pharmaceutics, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, China.
4
Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. Electronic address: 27507585@qq.com.
5
Institute of Orthopedics, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, China.

The essential role of GAPDH/Siah1 signaling pathway in the pathogenesis of various injurious conditions such as traumatic spinal cord injury (SCI) has been gradually recognized. However, the drugs targeting this signaling pathway are still lacking. The endocannabinoid system, including its receptors (CB1 and CB2), act as neuroprotective and immunomodulatory modulators in SCI. WIN55212-2, an agonist for CB1 and CB2 receptors, has been demonstrated with anti-inflammatory and anti-apoptotic effects in multiple neurological diseases. Therefore, the present study aimed to investigate whether WIN55212-2 could promote functional recovery after traumatic SCI via inhibition of the GAPDH/Siah1 signaling. The traumatic SCI was induced by dropping a 10-g impactor from 25 mm on the dorsal surface of T9 and T10. Our results showed that WIN55212-2 alleviated the activation of GAPDH/Siah1 signaling pathway after SCI, as indicated by the reduction in GAPDH nuclear expression, GAPDH-Siah1 complex formation and iNOS protein expression. Furthermore, WIN55212-2 reduced apoptosis, production of IL-1ß and TNF-a and activation of NF-?B signaling in the spinal cord after SCI. The behavioral tests showed that WIN55212-2 improved the functional recovery after traumatic SCI as indicated by sustained increase in the locomotor scores. However, these neuroprotective effects of WIN55212-2 were blocked in the presence of the combined treatment of AM630 (an antagonist of CB2) rather than AM251 (an antagonist of CB1). In conclusion, our study indicates that, WIN55212-2 improves the functional recovery after SCI via inhibition of GAPDH/Siah1 cascades in a CB2 receptor dependent manner, indicative of its therapeutic potential for traumatic SCI or other traumatic conditions.

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From: scaram(o)uche7/25/2017 10:54:38 AM
   of 435
 
Eur J Pharmacol. 2017 Jul 19. pii: S0014-2999(17)30491-0. doi: 10.1016/j.ejphar.2017.07.034. [Epub ahead of print]

Bidirectional allosteric interactions between cannabinoid receptor 1 (CB1) and dopamine receptor 2 long (D2L) heterotetramers.

Bagher AM1, Laprairie RB2, Toguri JT3, Kelly MEM4, Denovan-Wright EM5.

1
Department of Pharmacology, Dalhousie University, Halifax NS, Canada; Department of Pharmacology and Toxicology, King AbdulAziz University, Jeddah, KSA.
2
College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon SK, Canada.
3
Department of Pharmacology, Dalhousie University, Halifax NS, Canada.
4
Department of Pharmacology, Dalhousie University, Halifax NS, Canada; Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax NS, Canada.
5
Department of Pharmacology, Dalhousie University, Halifax NS, Canada. Electronic address: emdenova@dal.ca.

Type 1 cannabinoid (CB1) and dopamine 2 long form (D2L) receptors can physically interact to form heteromers that display unique pharmacology in vitro compared to homomeric complexes. Co-expression of CB1 and D2L and co-application of CB1 and D2 agonists increases cAMP levels while administration of either agonist alone decreases cAMP levels. To understand the observed co-agonist response, our first goal of the current study was to define the stoichiometry of CB1/D2L/Ga protein complexes. Using bioluminescence resonance energy transfer 2 (BRET2), we confirmed that, CB1 homodimers, D2L homodimers, and CB1/D2L heteromers are formed. By using sequential energy transfer 2 (SRET2) combined with bimolecular fluorescence complementation (BiFC), we were able to demonstrate that CB1/D2L form heterotetramers consisting of CB1 and D2L homodimers. We demonstrated that CB1/D2L heterotetramers are coupled to at least two Ga proteins. The second aim of the study was to investigate allosteric effects of a D2L agonist (quinpirole) on CB1 receptor function and to investigate the effects of a CB1 agonist [arachidonyl-2-chloroethylamide (ACEA)] on D2L receptor function within CB1/D2L heterotetramers. Treating cells co-expressing CB1 and D2L with both ACEA and quinpirole switched CB1 and D2L receptor coupling and signaling from Gai to Gas proteins, enhanced ß-arrestin1 recruitment and receptor co-internalization. The concept of bidirectional allosteric interaction within CB1/D2 heterotetramers has important implications for understanding the activity of receptor complexes in native tissues and under pathological conditions.

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From: scaram(o)uche7/30/2017 5:23:01 PM
   of 435
 
clinicaltrials.gov

"A growing body of physiological evidence now exists to support a potential role for inhaled cannabis in the medical management of adults with chronic obstructive pulmonary disease (COPD), particularly as it may related to improving pulmonary function, alleviating the symptom of breathlessness and improving exercise endurance. The purpose of this randomized double-blind crossover trials is to evaluate the efficacy and physiological mechanism(s) of action of inhaled vaporized cannabis targeted to relief of physical activity-related breathlessness and exercise endurance in symptomatic patients with severe-to-very severe COPD."

I've often wondered, and once, somewhere here at S.I., commented about COPD, pot versus cigarettes. But I know of no "body of physiological evidence". If anyone has a pointer, please point.

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From: scaram(o)uche8/11/2017 12:30:20 PM
   of 435
 
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
   of 435
 
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
   of 435
 
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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