Characterization of active and inactive states of CB1 receptor and the differential binding state modulation by cannabinoid agonists, antagonists and inverse agonists

Gullapalli, Srinivas; Amrutkar, Dipak Vasantrao; Gupta, S. K.; Kandadi, Machender R.; Kumar, Hemant; Gandhi, Maulik N.; Karande, Vikas; Narayanan, Shridhar

doi:10.1016/j.neuropharm.2010.03.001

Cited by 14 publications

(15 citation statements)

References 26 publications

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“…Non-specific binding was related mainly to binding to the glass fibre (data not shown). For the binding of 3 H]CP55,940 towards hCB1-CHO and hCB2-CHO cell membranes, K D values of 2.43 ± 1.89 nM ( n = 3) and 1.48 ± 0.88 nM ( n = 4) were determined in competitive binding experiments, which correspond with recently published data [37,38]. Kinetic analysis of the binding of 3 H]CP55,940 towards hCB2-CHO cell membranes revealed the rate constants k on = 0.266 × 10 9 M −1 min −1 and k off = 0.196 min −1 .…”

Section: Resultssupporting

confidence: 86%

Cannabinoid receptor type 2 (CB2)-selective N-aryl-oxadiazolyl-propionamides: synthesis, radiolabelling, molecular modelling and biological evaluation

et al. 2012

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BackgroundThe endocannabinoid system is involved in many physiological and pathological processes. Two receptors (cannabinoid receptor type 1 (CB1) and type 2 (CB2)) are known so far. Many unwanted psychotic side effects of inhibitors of this system can be addressed to the interaction with CB1. While CB1 is one of the most abundant neuroreceptors, CB2 is expressed in the brain only at very low levels. Thus, highly potent and selective compounds for CB2 are desired. N-aryl-((hetero)aromatic)-oxadiazolyl-propionamides represent a promising class of such selective ligands for the human CB2. Here, a library of various derivatives is studied for suitable routes for labelling with 18F. Such 18F-labelled compounds can then be employed as CB2-selective radiotracers for molecular imaging studies employing positron emission tomography (PET).ResultsBy varying the N-arylamide substructure, we explored the binding pocket of the human CB2 receptor and identified 9-ethyl-9H-carbazole amide as the group with optimal size. Radioligand replacement experiments revealed that the modification of the (hetero)aromatic moiety in 3-position of the 1,2,4-oxadiazoles shows only moderate impact on affinity to CB2 but high impact on selectivity towards CB2 with respect to CB1. Further, we could show by autoradiography studies that the most promising compounds bind selectively on CB2 receptors in mouse spleen tissue. Molecular docking studies based on a novel three-dimensional structural model of the human CB2 receptor in its activated form indicate that the compounds bind with the N-arylamide substructure in the binding pocket. 18F labelling at the (hetero)aromatic moiety at the opposite site of the compounds via radiochemistry was carried out.ConclusionsThe synthesized CB2-selective compounds have high affinity towards CB2 and good selectivity against CB1. The introduction of labelling groups at the (hetero)aromatic moiety shows only moderate impact on CB2 affinity, indicating the introduction of potential labelling groups at this position as a promising approach to develop CB2-selective ligands suitable for molecular imaging with PET. The high affinity for human CB2 and selectivity against human CB1 of the herein presented compounds renders them as suitable candidates for molecular imaging studies.

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Section: Resultssupporting

confidence: 86%

Cannabinoid receptor type 2 (CB2)-selective N-aryl-oxadiazolyl-propionamides: synthesis, radiolabelling, molecular modelling and biological evaluation

et al. 2012

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“…However, this does not necessarily mean that the tracers label exactly same receptor populations. A substantial portion of CB1R are known to undergo receptor internalization processes 49 , the CB1R exists in multiple affinity states in relation to agonist activity 65 , and appears to have many regulatory protein interactions 66 which increased to control levels after weeks of abstinence 38 . Chronic cannabis use similarly resulted in ~15% lower V T with [ C]OMAR.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Sex difference in brain CB1 receptor availability in man

et al. 2019

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“…Such high affinity PET-radioligands may allow in vivo visualization of the low density brain CB2 receptors. Moreover, agonists preferentially bind to cannabinoid receptors in their (functionally) activated conformation (Gullapalli et al, 2010 ). Therefore, agonist CB2 PET-radioligands may allow visualization of the activated fraction of the receptor which may correlate better with CB2 related pathology of the receptor system.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Biodistribution and In vitro Evaluation of Brain Permeable High Affinity Type 2 Cannabinoid Receptor Agonists [11C]MA2 and [18F]MA3

et al. 2016

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The type 2 cannabinoid receptor (CB2) is a member of the endocannabinoid system and is known for its important role in (neuro)inflammation. A PET-imaging agent that allows in vivo visualization of CB2 expression may thus allow quantification of neuroinflammation. In this paper, we report the synthesis, radiosynthesis, biodistribution and in vitro evaluation of a carbon-11 ([11C]MA2) and a fluorine-18 ([18F]MA3) labeled analog of a highly potent N-arylamide oxadiazole CB2 agonist (EC50 = 0.015 nM). MA2 and MA3 behaved as potent CB2 agonist (EC50: 3 nM and 0.1 nM, respectively) and their in vitro binding affinity for hCB2 was found to be 87 nM and 0.8 nM, respectively. Also MA3 (substituted with a fluoro ethyl group) was found to have higher binding affinity and EC50 values when compared to the originally reported trifluoromethyl analog 12. [11C]MA2 and [18F]MA3 were successfully synthesized with good radiochemical yield, high radiochemical purity and high specific activity. In mice, both tracers were efficiently cleared from blood and all major organs by the hepatobiliary pathway and importantly these compounds showed high brain uptake. In conclusion, [11C]MA2 and [18F]MA3 are shown to be high potent CB2 agonists with good brain uptake, these favorable characteristics makes them potential PET probes for in vivo imaging of brain CB2 receptors. However, in view of its higher affinity and selectivity, further detailed evaluation of MA3 as a PET tracer for CB2 is warranted.

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Characterization of active and inactive states of CB1 receptor and the differential binding state modulation by cannabinoid agonists, antagonists and inverse agonists

Cited by 14 publications

References 26 publications

Cannabinoid receptor type 2 (CB2)-selective N-aryl-oxadiazolyl-propionamides: synthesis, radiolabelling, molecular modelling and biological evaluation

Cannabinoid receptor type 2 (CB2)-selective N-aryl-oxadiazolyl-propionamides: synthesis, radiolabelling, molecular modelling and biological evaluation

Sex difference in brain CB1 receptor availability in man

Synthesis, Biodistribution and In vitro Evaluation of Brain Permeable High Affinity Type 2 Cannabinoid Receptor Agonists [11C]MA2 and [18F]MA3

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