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Novel 1 ',1 '-Chain Substituted Hexahydrocannabinols: 9/beta-1-Hydroxy-3-(1-hexyl-cyclobut-l-yl)hexahydrocannabinol (AM2389) a Highly Potent Cannabinoid Receptor 1 (CB1) Agonist

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Novel 1 ',1 '-Chain Substituted Hexahydrocannabinols: 9/beta-1-Hydroxy-3-(1-hexyl-cyclobut-l-yl)hexahydrocannabinol (AM2389) a Highly Potent Cannabinoid Receptor 1 (CB1) Agonist
Paronis, Carole A.
Halikhedkar, Aneetha
Papanastasiou, Ioannis
Παπαχατζής, Δημήτρης Π.
Shukla, Vidyanand G.
Bowman, Anna L.
Han, Xiuwen
Makriyannis, Alexandros
Nikas, Spyros P.
Alapafuja, Shakiru O.
Άρθρο σε επιστημονικό περιοδικό
2010-10-14
WASHINGTON
In pursuit of a more detailed understanding of the structural requirements for the key side chain cannabinoid pharmacophore, we have extended our SA R to cover a variety of conformationally modified side chains within the 9-keto and 9-hydroxyl tricyclic structures. OF the compounds described here. those with a seven-atom long side chain substituted with a cyclopentyl ring at Cl' position have very high affinities For both CB1 and CB2 (0.97 nM < K(1) < 5.25 nM), with no preference for either of the two receptors. However, presence of the smaller cyclobutyl group at the Cl' position leads to an optimal affinity and selectivity interaction with CB1. Thus, two of the Cl'-cyclobutyl analogues, namely. (6a R.10aR R)-3-(1-hexyl-cyclobut-1-y1)-6,6a,7,8, 10,10a-hexahydro-1-hydroxy-6,6-dimethyl-9H-dibenzo-[b,d]pyran-9-one and (6aR,9R, 10aR)-3-(1-hexyl-cyclobut-1-yl)-6a,7,8,9,10, 10a-hexahydro-6.6-dimethyl-6H-dibenzo[b,d]pyran-1,9 diol (7e-beta, AM2389), exhibited remarkably high affinities (0.84 and 0.16 nM respectively) and significant selectivities (16- and 26-fold, respectively) for CB1. Compound 7e-beta was found to exhibit exceptionally high in vitro and in vivo potency with a relatively long duration of action.
Χημεία (Γενικά) (EL)
Φαρμακευτική (EL)
Pharmacy and materia medica (EN)
Chemistry (General) (EN)
Chemistry, Medicinal
English
American Chemical Society
Journal of Medicinal Chemistry
© AMER CHEMICAL SOC
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© AMER CHEMICAL SOC (EN)
National Hellenic Research Foundation (NHRF)
Helios - Repository of the National Hellenic Research Foundation (NHRF)



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