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Oximes short-acting CB1 receptor agonists.

Michael S Malamas1, Jimit Girish Raghav1, Xiaoyu Ma1

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

Bioorganic & Medicinal Chemistry
|August 21, 2018
PubMed
Summary

New oxime analogs of THC were synthesized to reduce hydrophobicity and alter duration of action. The trans-oxime 8a showed a fast onset and short duration, limiting side effects and selected for anorexia nervosa studies.

Keywords:
(-)-Δ(9)-Tetrahydrocannabinol2-Arachidonoylglycerol (2-AG)AnalgesiaAnorexia Nervosa (AN)Arachidonoylethanolamine (AEA)CB1CB2GPCRcannabinoid receptorsΔ(8)-THCΔ(8)-THC-DMHΔ(9)-THC

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Area of Science:

  • Medicinal Chemistry
  • Pharmacology
  • Computational Chemistry

Background:

  • Cannabinoid receptor 1 (CB1) agonists, like Δ8-THC, have therapeutic potential but are limited by long duration and side effects.
  • Modulating physicochemical properties such as hydrophobicity (log P) and topological surface area (tPSA) can impact drug distribution and duration of action.

Purpose of the Study:

  • To synthesize novel oxime analogs of Δ8-THC with altered hydrophobicity and duration of action.
  • To investigate the CB1 and CB2 receptor activity, including agonism, antagonism, and inverse agonism.
  • To evaluate the in vivo pharmacological effects and explore the binding mechanisms using molecular dynamics simulations.

Main Methods:

  • Synthesis of novel oxime analogs by introducing internal oximes and polar groups at the C3 alkyl tail of Δ8-THC.
  • In vitro functional assays (cAMP) to determine CB1 and CB2 receptor activity (agonist, antagonist, inverse agonist).
  • In vivo behavioral studies (analgesia, hypothermia) to assess pharmacological effects and duration.
  • 100 ns molecular dynamic (MD) simulations of CB1 receptor complexes with synthesized oximes.

Main Results:

  • Synthesized oxime analogs exhibited sub-nanomolar CB1 affinity with significantly reduced hydrophobicity (ClogP 2.5-3.5).
  • Trans-oximes acted as CB1 agonists, while cis-oximes acted as neutral antagonists.
  • All analogs showed CB2 receptor affinity but functioned as inverse agonists.
  • Trans-oxime 8a demonstrated a fast onset (20 min) and short duration (180 min) of action, contrasting with prolonged effects of Δ8-THC-DMH.
  • MD simulations revealed distinct binding modes for cis and trans isomers, explaining their functional effects.

Conclusions:

  • Novel oxime analogs offer tunable CB1 receptor modulation with reduced hydrophobicity and predictable short duration of action.
  • Trans-oxime 8a's favorable pharmacodynamic profile makes it a promising candidate for pre-clinical evaluation in anorexia nervosa.
  • The study elucidates structure-activity relationships and binding mechanisms for CB1 receptor modulation.