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meta-Directing Deactivators: –NO2, –CN, –CHO, –⁠CO2R, –COR, –CO2H01:13

meta-Directing Deactivators: –NO2, –CN, –CHO, –⁠CO2R, –COR, –CO2H

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All meta-directing substituents are deactivating groups. These substituents withdraw electrons from the aromatic ring, making the ring less reactive toward electrophilic substitution. For example, the nitration of nitrobenzene is 100,000 times slower than that of benzene because of the deactivating effect of the nitro group. The first step in an electrophilic aromatic substitution is the addition of an electrophile to form a resonance-stabilized carbocation. The energy diagrams for...
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ortho–para-Directing Deactivators: Halogens01:24

ortho–para-Directing Deactivators: Halogens

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Halogens are ortho–para directors. They are more electronegative than carbon. Therefore, as ring substituents, they can withdraw electrons through the inductive effect and deactivate the aromatic ring towards electrophilic substitution. Halogens also have an electron-donating resonance effect on the ring, which influences the orientation of the incoming electrophile. If an electrophile attacks at the ortho or the para position, the halogen donates electrons and stabilizes the intermediate...
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ortho–para-Directing Activators: –CH3, –OH, –⁠NH2, –OCH301:11

ortho–para-Directing Activators: –CH3, –OH, –⁠NH2, –OCH3

7.9K
All ortho–para directors, excluding halogens, are activating groups. These groups donate electrons to the ring, making the ring carbons electron-rich. Consequently, the reactivity of the aromatic ring towards electrophilic substitution increases. For instance, the nitration of anisole is about 10,000 times faster than the nitration of benzene. The electron-donating effect of the methoxy group in anisole activates the ortho and para positions on the ring and stabilizes the corresponding...
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Radical Chain-Growth Polymerization: Overview01:10

Radical Chain-Growth Polymerization: Overview

3.7K
Chain-growth or addition polymerization is successive addition reactions of monomers with a polymer chain. In radical chain-growth polymerization, the reaction proceeds via a free-radical intermediate. The free radical is formed from radical initiators, which spontaneously generate free radicals by homolytic fission. Organic peroxides (such as dibenzoyl peroxide, as shown in Figure 1) or azo compounds are popular radical initiators. A low concentration ratio of radical initiator to monomer is...
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Radical Reactivity: Intramolecular vs Intermolecular01:33

Radical Reactivity: Intramolecular vs Intermolecular

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Radical reactions can occur either intermolecularly or intramolecularly. In an intermolecular radical reaction, a nucleophilic radical adds to an electrophilic alkene or vice versa. In such reactions, the radical and generally the alkene, which is also called the radical trap, are two different molecules. Additionally, for such intermolecular reactions to occur, the radical trap must be active, present in an excess concentration, and the radical starting material must have a weak...
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Radical Chain-Growth Polymerization: Mechanism01:09

Radical Chain-Growth Polymerization: Mechanism

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The radical chain-growth polymerization mechanism consists of three steps: initiation, propagation, and termination of polymerization. The polymerization initiates when a free radical generated from the radical initiator adds to the unsaturated bond in the monomer. The unpaired electron of the free radical and one π electron in the unsaturated bond creates a σ bond between the free radical and the monomer. As a result, the other π electron in the unsaturated bond converts this species into...
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Preparation of a Corannulene-functionalized Hexahelicene by CopperI-catalyzed Alkyne-azide Cycloaddition of Nonplanar Polyaromatic Units
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Novel C-Ring-Hydroxy-Substituted Controlled Deactivation Cannabinergic Analogues.

Shashank Kulkarni1, Spyros P Nikas1, Rishi Sharma1

  • 1Center for Drug Discovery, Department of Chemistry and Chemical Biology, and Department of Pharmaceutical Sciences, Northeastern University , Boston, Massachusetts 02115, United States.

Journal of Medicinal Chemistry
|July 2, 2016
PubMed
Summary
This summary is machine-generated.

Researchers developed novel, controlled-deactivation cannabinoids with high potency and short action duration. These new analogues, including lead molecule AM7499, show promise for safer cannabinoid therapeutics in preclinical studies.

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Area of Science:

  • Medicinal Chemistry
  • Pharmacology
  • Drug Discovery

Background:

  • Cannabinoids, including hexahydrocannabinol (HHC) and tetrahydrocannabinol (THC), are widely studied for therapeutic potential.
  • Developing cannabinoid analogues with controlled deactivation, high potency, and short duration of action is a key research goal.
  • Existing cannabinoid agonists may have limitations regarding duration of action and safety profiles.

Purpose of the Study:

  • To design, synthesize, and pharmacologically evaluate novel C9- and C11-hydroxy-substituted HHC and THC analogues.
  • To investigate the impact of a metabolically labile 2',3'-ester group on the side chain for controlled deactivation.
  • To identify lead cannabinoid molecules with improved potency and duration of action compared to classical agonists.

Main Methods:

  • Synthesis of novel hexahydrocannabinol (HHC) and tetrahydrocannabinol (THC) analogues with specific hydroxyl substitutions and esterified side chains.
  • In vitro pharmacological evaluation to assess binding affinity and functional activity of the synthesized compounds.
  • In vivo studies in rodents and non-human primates to validate the controlled deactivation approach and assess pharmacokinetic/pharmacodynamic profiles.

Main Results:

  • Successful design and synthesis of C9- and C11-hydroxy-substituted HHC and THC analogues.
  • Identification of a lead molecule, butyl-2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl]-2-methylpropanoate (AM7499), with high in vitro and in vivo potency.
  • Demonstration of a shorter duration of action for AM7499 compared to existing classical cannabinoid agonists.
  • Validation of the controlled deactivation strategy through in vivo studies in preclinical models.

Conclusions:

  • The developed cannabinoid analogues, particularly AM7499, represent a promising advancement in controlled-deactivation cannabinoid therapeutics.
  • These novel compounds offer high potency and a desirable short duration of action, potentially leading to improved safety and efficacy.
  • The findings support the potential of metabolically labile ester groups for fine-tuning cannabinoid pharmacokinetics and pharmacodynamics.