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Biotech / Medical : Indications -- obesity/erectile dysfunction

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From: scaram(o)uche9/17/2018 3:04:44 PM
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J Med Chem. 2018 Sep 10. doi: 10.1021/acs.jmedchem.8b00611. [Epub ahead of print]

(R)-N-(1-Methyl-2-hydroxyethyl)-13-(S)-methyl-arachidonamide (AMG315): A Novel Chiral Potent Endocannabinoid Ligand with Stability to Metabolizing Enzymes.

Liu Y, Ji L, Eno M, Kudalkar S, Li A, Schimpgen M, Benchama O, Morales P, Xu S, Hurst DP, Wu S, Mohammad KA, Wood JT, Zvonok N, Papahatjis D, Zhou H, Honrao C, Mackie K, Reggio PH, Hohmann A, Marnett LJ, Makriyannis A, Nikas SP.

The synthesis of potent metabolically stable endocannabinoids is challenging. Here we report a chiral arachidonoyl ethanolamide (AEA) analog, namely, (13S, 1'R)-dimethylanandamide (AMG315, 3a) a high affinity ligand for the CB1 receptor (Ki of 7.8 ± 1.4 nM) that behaves as a potent CB1 agonist in vitro (EC50 = 0.6 ± 0.2 nM). (13S, 1'R)-dimethylanandamide is the first potent AEA analog with significant stability for all endocannabinoid hydrolyzing enzymes as well as the oxidative enzymes COX-2. When tested in vivo using the CFA-induced inflammatory pain model 3a behaved as a more potent analgesic when compared to endogenous AEA or its hydrolytically stable analog AM356. This novel analog will serve as a very useful endocannabinoid probe.

Biochem Pharmacol. 2018 Sep 5. pii: S0006-2952(18)30382-4. doi: 10.1016/j.bcp.2018.08.046. [Epub ahead of print]

Cannabidiol skews biased agonism at cannabinoid CB1 and CB2 receptors with smaller effect in CB1-CB2 heteroreceptor complexes.

Navarro G1, Reyes-Resina I2, Rivas-Santisteban R2, Sánchez de Medina V3, Morales P4, Casano S3, Ferreiro-Vera C3, Lillo A5, Aguinaga D5, Jagerovic N4, Nadal X6, Franco R7.
1
Molecular Neurobiology laboratory, Department of Biochemistry and Physiology, Universitat de Barcelona. Barcelona, Spain; Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III. Madrid, Spain.
2
Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III. Madrid, Spain; Molecular Neurobiology laboratory, Department of Biochemistry and Molecular Biomedicine, Universitat de Barcelona. Barcelona, Spain.
3
Phytoplant Research S.L., Córdoba, Spain.
4
Instituto de Química Médica, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
5
Molecular Neurobiology laboratory, Department of Biochemistry and Molecular Biomedicine, Universitat de Barcelona. Barcelona, Spain.
6
Phytoplant Research S.L., Córdoba, Spain. Electronic address: x.nadal@phytoplant.es.
7
Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III. Madrid, Spain; Molecular Neurobiology laboratory, Department of Biochemistry and Molecular Biomedicine, Universitat de Barcelona. Barcelona, Spain.

Currently, biased agonism is at the center stage of drug development approaches. We analyzed effects of a battery of cannabinoids plus/minus cannabidiol (CBD) in four functional parameters (cAMP levels, phosphorylation of extracellular signal-regulated kinases (ERK1/2), ß-arrestin recruitment and label-free/DMR) in HEK-293T cells expressing cannabinoid receptors, CB1 or CB2, or CB1-CB2 heteroreceptor complexes. In all cases two natural agonists plus two selective synthetic agonists were used. Furthermore, the effect of cannabidiol, at a dose (100 nM) that does not allow significant binding to the orthosteric center of either receptor, was measured. From the huge amount of generated data, we would like to highlight that the two psychotropic molecules (?9-tetrahydrocannabinol/THC and CP-55940) showed similar bias in CB1R and that the bias of THC was particularly relevant toward MAPK pathway. Furthermore, THC did not activate the Gi protein coupled to CB2R. Interestingly, the biased agonism was reduced when assays were performed in cells expressing the two receptors, thus suggesting that the heteromer allows less functional selectivity. In terms of cannabidiol action, the phytocannabinoid altered the functional responses, likely by allosteric means, and modified potency, agonist IC50/EC50 values and biased agonism in qualitative and/or quantitative different ways depending on the agonist. The effect of cannabidiol on anandamide actions on both cannabinoid receptors was particularly noteworthy as was significantly different from that of other compounds. Results are a compendium of data on biased agonism on cannabinoid receptors in the absence and presence of cannabidiol. In addition, for the first time, GPCR biased agonism is characterized in an heteromeric context.
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