Pharmacophoric requirements for cannabinoid side chains: multiple bond and C1'-substituted delta 8-tetrahydrocannabinols

Journal of Medicinal Chemistry
D PapahatjisA Makriyannis

Abstract

Accumulated evidence indicates that within the cannabinoid structure the aliphatic side chain plays a pivotal role in determining cannabimimetic activity. We describe the synthesis and affinities for the CB1 and CB2 receptors of a series of novel delta 8-THC analogues in which the side-chain pharmacophores are conformationally more defined than in the parent molecule. No analogue has the side-chain pharmacophore in a fully restricted conformation. However, our design serves to narrow down the scope of options for conformational requirements at the receptor active sites. All the analogues tested showed nanomolar or subnanomolar affinities for the receptors; 2-(6a,7,10,10a-tetrahydro-6,6,9-trimethyl-1-hydroxy-6H- dibenzo[b,d]pyranyl)-2-hexyl-1,3-dithiolane was found to possess very high affinity for both cannabinoid receptors (CB1, Ki = 0.32 nM; CB2, Ki = 0.52 nM).

References

Dec 11, 1990·Nucleic Acids Research·C GérardM Parmentier
Jan 1, 1990·Life Sciences·A Makriyannis, R S Rapaka
Jun 30, 1972·The Journal of Organic Chemistry·K E Fahrenholtz
Jun 10, 1994·Journal of Medicinal Chemistry·V AbadjiA Makriyannis
Oct 25, 1996·Journal of Medicinal Chemistry·A D KhanolkarA Makriyannis

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Citations

Dec 7, 2000·Chemistry and Physics of Lipids·A D KhanolkarA Makriyannis
Dec 31, 2002·Chemistry and Physics of Lipids·Sonya L PalmerAlexandros Makriyannis
Aug 17, 2002·Pharmacology & Therapeutics·Andreas Goutopoulos, Alexandros Makriyannis
Nov 22, 2002·Bioorganic & Medicinal Chemistry Letters·Demetris P PapahatjisAlexandros Makriyannis
Sep 25, 2003·Bioorganic & Medicinal Chemistry Letters·Mathangi KrishnamurthyBob M Moore
Aug 28, 1999·Bioorganic & Medicinal Chemistry Letters·A D KhanolkarA Makriyannis
Jul 3, 2010·Journal of Medicinal Chemistry·Darryl D DixonAlexandros Makriyannis
Mar 12, 2005·The AAPS Journal·Spyros P NikasAlexandros Makriyannis
Oct 26, 2005·Life Sciences·Ganesh A ThakurAlexandros Makriyannis
Jul 5, 2005·Life Sciences·Lea W Padgett
Nov 6, 2007·Bioorganic & Medicinal Chemistry Letters·Serdar DurdagiThomas Mavromoustakos
Jul 12, 2016·Perspectives in Medicinal Chemistry·Eric W Bow, John M Rimoldi
Aug 23, 2007·Chemistry & Biodiversity·Eric Stern, Didier M Lambert
Dec 5, 2002·The Journal of Peptide Research : Official Journal of the American Peptide Society·R P PiconeA Makriyannis
Aug 12, 2020·Chemistry : a European Journal·Anderson R AguillónRodrigo O M A de Souza
Jun 19, 2001·Biochimica Et Biophysica Acta·T MavromoustakosP Laggner
Jul 11, 2003·Journal of Medicinal Chemistry·Demetris P PapahatjisAlexandros Makriyannis
Aug 4, 2007·Journal of Medicinal Chemistry·Demetris P PapahatjisAlexandros Makriyannis
Jul 8, 2005·Journal of Medicinal Chemistry·Dai LuAlexandros Makriyannis

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