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Pharmacological Comparisons Between Cannabidiol and KLS-13019.
J Mol Neurosci. 2018 Sep; 66(1):121-134.JM

Abstract

Cannabidiol (CBD) exhibits neuroprotective properties in many experimental systems. However, development of CBD as a drug has been confounded by the following: (1) low potency; (2) a large number of molecular targets; (3) marginal pharmacokinetic properties; and (4) designation as a schedule 1 controlled substance. The present work compared the properties of CBD with a novel molecule (KLS-13019) that has structural similarities to CBD. The design strategy for KLS-13019 was to increase hydrophilicity while optimizing neuroprotective potency against oxidative stress toxicity relevant to hepatic encephalopathy. The protective responses of CBD and KLS-13019 were compared in dissociated rat hippocampal cultures co-treated with toxic levels of ethanol and ammonium acetate. This comparison revealed that KLS-13019 was 31-fold more potent than CBD in preventing neuronal toxicity from the combined toxin treatment, while both compounds exhibited complete protective efficacy back to control values. In addition, treatment with KLS-13019 alone was 5-fold less toxic (TC50) than CBD. Previous studies suggested that CBD targeted the Na+-Ca2+ exchanger in mitochondria (mNCX) to regulate intracellular calcium levels, an important determinant of neuronal survival. After treatment with an inhibitor of mNCX (CGP-37157), no detectable neuroprotection from ethanol toxicity was observed for either CBD or KLS-13019. Furthermore, AM630 (CB2 antagonist) significantly attenuated CBD-mediated neuroprotection, while having no detectable effect on neuroprotection from KLS-13019. Our studies indicated KLS-13019 was more potent and less toxic than CBD. Both compounds can act through mNCX. KLS-13019 may provide an alternative to CBD as a therapeutic candidate to treat diseases associated with oxidative stress.

Authors+Show Affiliations

Advanced Neural Dynamics, Inc, Pennsylvania Biotechnology Center, 3805 Old Easton Road, Doylestown, PA, 18902, USA. dbrenneman@advneuraldynamics.com. Kannalife Sciences, Inc, Pennsylvania Biotechnology Center, Doylestown, PA, 18902, USA. dbrenneman@advneuraldynamics.com.Kannalife Sciences, Inc, Pennsylvania Biotechnology Center, Doylestown, PA, 18902, USA.Kannalife Sciences, Inc, Pennsylvania Biotechnology Center, Doylestown, PA, 18902, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30109468

Citation

Brenneman, Douglas E., et al. "Pharmacological Comparisons Between Cannabidiol and KLS-13019." Journal of Molecular Neuroscience : MN, vol. 66, no. 1, 2018, pp. 121-134.
Brenneman DE, Petkanas D, Kinney WA. Pharmacological Comparisons Between Cannabidiol and KLS-13019. J Mol Neurosci. 2018;66(1):121-134.
Brenneman, D. E., Petkanas, D., & Kinney, W. A. (2018). Pharmacological Comparisons Between Cannabidiol and KLS-13019. Journal of Molecular Neuroscience : MN, 66(1), 121-134. https://doi.org/10.1007/s12031-018-1154-7
Brenneman DE, Petkanas D, Kinney WA. Pharmacological Comparisons Between Cannabidiol and KLS-13019. J Mol Neurosci. 2018;66(1):121-134. PubMed PMID: 30109468.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacological Comparisons Between Cannabidiol and KLS-13019. AU - Brenneman,Douglas E, AU - Petkanas,Dean, AU - Kinney,William A, Y1 - 2018/08/14/ PY - 2018/07/20/received PY - 2018/08/03/accepted PY - 2018/8/16/pubmed PY - 2018/11/10/medline PY - 2018/8/16/entrez KW - Cannabidiol KW - Cannabis KW - Ethanol KW - Hippocampal cultures KW - Mitochondrial Na+-Ca2+ exchanger KW - Neuroprotection KW - Oxidative stress SP - 121 EP - 134 JF - Journal of molecular neuroscience : MN JO - J Mol Neurosci VL - 66 IS - 1 N2 - Cannabidiol (CBD) exhibits neuroprotective properties in many experimental systems. However, development of CBD as a drug has been confounded by the following: (1) low potency; (2) a large number of molecular targets; (3) marginal pharmacokinetic properties; and (4) designation as a schedule 1 controlled substance. The present work compared the properties of CBD with a novel molecule (KLS-13019) that has structural similarities to CBD. The design strategy for KLS-13019 was to increase hydrophilicity while optimizing neuroprotective potency against oxidative stress toxicity relevant to hepatic encephalopathy. The protective responses of CBD and KLS-13019 were compared in dissociated rat hippocampal cultures co-treated with toxic levels of ethanol and ammonium acetate. This comparison revealed that KLS-13019 was 31-fold more potent than CBD in preventing neuronal toxicity from the combined toxin treatment, while both compounds exhibited complete protective efficacy back to control values. In addition, treatment with KLS-13019 alone was 5-fold less toxic (TC50) than CBD. Previous studies suggested that CBD targeted the Na+-Ca2+ exchanger in mitochondria (mNCX) to regulate intracellular calcium levels, an important determinant of neuronal survival. After treatment with an inhibitor of mNCX (CGP-37157), no detectable neuroprotection from ethanol toxicity was observed for either CBD or KLS-13019. Furthermore, AM630 (CB2 antagonist) significantly attenuated CBD-mediated neuroprotection, while having no detectable effect on neuroprotection from KLS-13019. Our studies indicated KLS-13019 was more potent and less toxic than CBD. Both compounds can act through mNCX. KLS-13019 may provide an alternative to CBD as a therapeutic candidate to treat diseases associated with oxidative stress. SN - 1559-1166 UR - https://www.unboundmedicine.com/medline/citation/30109468/Pharmacological_Comparisons_Between_Cannabidiol_and_KLS_13019_ L2 - https://dx.doi.org/10.1007/s12031-018-1154-7 DB - PRIME DP - Unbound Medicine ER -