Classical/non-classical cannabinoid hybrids; stereochemical requirements for the southern hydroxyalkyl chain.
We have synthesized a range of hybrid classical/non-classical cannabinoids (CC/NCCs) combining the hexahydrocannabinol dibenzopyran structure with the hydroxyalkyl chain found in CP-55940, in order to investigate the role of the hydroxyalkyl pharmacophore in cannabimimetic activity. This was achieved by synthesizing CC analogs in which the 6 alpha- and 6 beta-methyl groups were modified to the corresponding hydroxyethyl groups. Our binding data indicated that beta position was the preferred orientation for the hydroxyalkyl moiety, affinity for the CB1 receptor being 20-fold greater for the 6 beta-hydroxyethyl than the corresponding 6 alpha-analog. Further studies using 6 beta-hydroxyalkyldibenzopyran analogs varying the southern aliphatic chain length from 6 beta-hydroxymethyl to 6 beta-hydroxyethyl to 6 beta-hydroxypropyl demonstrated little potency change with chain length. Therefore, we concluded that whilst the hydroxyalkyl pharmacophore was strongly affected by its configuration relative to the dibenzopyran ring, the chain length of the hydroxyalkyl moiety (up to the n = 3 homolog) was not critical.
Tius
M A
MA
Department of Chemistry, University of Hawaii, Honolulu 96822, USA.
Hill
W A
WA
Zou
X L
XL
Busch-Petersen
J
J
Kawakami
J K
JK
Fernandez-Garcia
M C
MC
Drake
D J
DJ
Abadji
V
V
Makriyannis
A
A
D000818:Animals; D001667:Binding, Competitive; D002186:Cannabinoids / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D003511:Cyclohexanols / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D066298:In Vitro Techniques; D016548:Prosencephalon / Q000378:metabolism; D051381:Rats; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D002186:Cannabinoids; D003511:Cyclohexanols; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol