2008
DOI: 10.1021/jm8005299
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Abstract: Structure-activity relationship studies of classical cannabinoid analogs have established that the C3 aliphatic side chain plays a pivotal role in determining cannabinergic potency. In earlier work we provided evidence for the presence of subsites within the CB1 and CB2 cannabinoid receptor binding domains that can accommodate bulky conformationally defined substituents at the C3 alkyl side chain pharmacophore of classical cannabinoids. We have now extended this work with the synthesis of a series of Δ8-THC an… Show more

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Cited by 26 publications
(24 citation statements)
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References 46 publications
(80 reference statements)
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“…Both 1c and 1b have greater CB2 affinity than 1a , but 1c also has inverted selectivity compared to 1a , with a 10-fold preference for CB2 over CB1. 5 These data suggested that small structural modifications of the adamantyl group may lead to substantial variations in the overall pharmacological profiles within this class of analogues. This motivated us to further explore the pharmacophoric features of these unusual cannabinoids in which the flexible side chain of their classical structure has been substituted by conformationally fixed cyclic substituents.…”
Section: Introductionmentioning
confidence: 95%
See 1 more Smart Citation
“…Both 1c and 1b have greater CB2 affinity than 1a , but 1c also has inverted selectivity compared to 1a , with a 10-fold preference for CB2 over CB1. 5 These data suggested that small structural modifications of the adamantyl group may lead to substantial variations in the overall pharmacological profiles within this class of analogues. This motivated us to further explore the pharmacophoric features of these unusual cannabinoids in which the flexible side chain of their classical structure has been substituted by conformationally fixed cyclic substituents.…”
Section: Introductionmentioning
confidence: 95%
“…4 endo -Norbornyl cannabinoid 1b (AM735) 5 and exo -norbornyl 1c (AM731) 5 underscore some of the subtleties inherent in this structural motif. Both 1c and 1b have greater CB2 affinity than 1a , but 1c also has inverted selectivity compared to 1a , with a 10-fold preference for CB2 over CB1.…”
Section: Introductionmentioning
confidence: 99%
“…This route (Scheme 2) utilized a Grignard reaction with (1 R )-(+)-camphor to prepare both endo -(bornyl) and exo -(isobornyl) 2-(3,5-dimethoxyphenyl)-1,7,7-trimethylbicyclo-[2.2.1]heptane analogs, 6 and 7 , respectively, that were synthetic intermediates for a new series of classical cannabinoid analogs. 15 The Grignard reagent prepared from 1-chloro-3,5-dimethoxybenzene ( 4 ) reacted with (1 R )-(+)-camphor to give a 2:1 mixture of 3,5-dimethoxyphenyl adducts 5 that was inseparable by both flash column chromatography and chiral HPLC, though we were able to achieve separation after the subsequent step. The reported Grignard reaction of a preformed complex of (1 R )-(+)-camphor with cerium(III) chloride 16,17 that gives endo -adducts exclusively was not used as both endo - and exo -adducts were desired.…”
Section: Resultsmentioning
confidence: 95%
“…It is, however, known that the biological activity of chiral phenols depends substantially on the configuration of their chiral cen ters [5][6][7].…”
Section: Introductionmentioning
confidence: 99%