The Cannabis Papers: A citizen’s guide to cannabinoids (2011)
2014 Cannabinoid Champions ~ Bivalency and Heteronomy
Publius’ 2014 cannabinoid science champions, Bivalency (it doubles) and Heteronomy (not autonomous), are spotlighted for their contributions to future knowledge. Both are CS homeostatic processes within the human body that work without notice or acclaim. Forward looking to 2015 and beyond, bivalency and heteronomy are cannabinoid science players with a high-knowledge upside. For now, here are four 2014 PubMed articles discussing: heteromerization and CB2, unexpected (intrinsic) bivalent CS properties, and two on Orexin, involved in arousal, wakefulness and appetite, and CB1 heterodimers and heteromeric signaling complexes.
I. Heteromerization of GPR55 and CB2 to form Unique Signaling Units
“Heteromerization of GPCRs is key to the integration of extracellular signals and the subsequent cell response via several mechanisms including heteromer-selective ligand binding, trafficking and/or downstream signalling. As the lysophosphatidylinositol GPCR 55 (GPR55) has been shown to affect the function of the cannabinoid receptor subtype 2 (CB2 receptor) in human neutrophils, we investigated the possible heteromerization of CB2 receptors with GPR55. … Heteromers, unique signalling units, form in HEK293 cells expressing GPR55 and CB2 receptors.”
Heteromerization of GPR55 and cannabinoid CB2 receptors modulates signalling.
Balenga NA, Martínez-Pinilla E, Kargl J, Schröder R, Peinhaupt M, Platzer W, Bálint Z, Zamarbide M, Dopeso-Reyes IG, Ricobaraza A, Pérez-Ortiz JM, Kostenis E, Waldhoer M, Heinemann A, Franco R.
Br J Pharmacol. 2014 Dec;171(23):5387-406. doi: 10.1111/bph.12850. Epub 2014 Sep 5.
PMID: 25048571 [PubMed - in process]
II. Bivalent Cannabinoid Receptor Ligands and Unexpected Intrinsic Properties
“The design of bivalent ligands targeting G protein-coupled receptors (GPCRs) often leads to the development of new, highly selective and potent compounds. To date, no bivalent ligands for the human cannabinoid receptor type 2 (hCB₂R) of the endocannabinoid system (ECS) are described. Therefore, two sets of homobivalent ligands containing as parent structure the hCB2R selective agonist 13a and coupled at different attachment positions were synthesized. Changes of the parent structure at these positions have a crucial effect on the potency and efficacy of the ligands. However, we discovered that bivalency has an influence on the effect at both cannabinoid receptors. Moreover, we found out that the spacer length and the attachment position altered the efficacy of the bivalent ligands at the receptors by turning agonists into antagonists and inverse agonists.”
Synthesis and biological evaluation of bivalent cannabinoid receptor ligands based on hCB₂R selective benzimidazoles reveal unexpected intrinsic properties.
Nimczick M, Pemp D, Darras FH, Chen X, Heilmann J, Decker M.
Bioorg Med Chem. 2014 Aug 1;22(15):3938-46. doi: 10.1016/j.bmc.2014.06.008. Epub 2014 Jun 13.
PMID: 24984935 [PubMed - in process]
III. Orexin OX1 and Cannabinoid CB1 Heterodimers and Oligomers
“Cannabinoid CB1 and orexin OX1 receptors have been suggested to form heterodimers and oligomers. … Bivalent ligands targeting CB1-OX1 receptor dimers could be potentially useful as a tool for further exploring the roles of such heterodimers in vitro and in vivo.”
Toward the Development of Bivalent Ligand Probes of Cannabinoid CB1 and Orexin OX1 Receptor Heterodimers.
Perrey DA, Gilmour BP, Thomas BF, Zhang Y.
ACS Med Chem Lett. 2014 Mar 25;5(6):634-8. doi: 10.1021/ml4004759. eCollection 2014 Jun 12.
PMID: 24944734 [PubMed]
IV. Heteromeric Complexes, Orexin OX1 and Cannabinoid CB1 Receptors
“Human OX1 orexin receptors have been shown to homodimerize and they have also been suggested to heterodimerize with CB1 cannabinoid receptors. The latter has been suggested to be important for orexin receptor responses and trafficking. … As orexin receptors efficiently signal via endocannabinoid production to CB1 receptors, dimerization could be an effective way of forming signal complexes with optimal cannabinoid concentrations available for cannabinoid receptors.”
Human orexin/hypocretin receptors form constitutive homo- and heteromeric complexes with each other and with human CB1 cannabinoid receptors.
Jäntti MH, Mandrika I, Kukkonen JP.
Biochem Biophys Res Commun. 2014 Mar 7;445(2):486-90. doi: 10.1016/j.bbrc.2014.02.026. Epub 2014 Feb 13.
PMID: 24530395 [PubMed - indexed for MEDLINE]
Video: Cannabinoid System in Neuroprotection, Raphael Mechoulam PhD
Happy New Year and a Forward Looking 2015 ~ Thanks All!
Posted by Bryan W. Brickner