Pharmacological evaluation of halogenated Δ8-THC analogs

Charalambous, Avgui; Lin, Sonyuan; Marciniak, Gilbert; Banijamali, Ali R.; Friend, F.L.; Compton, David R.; Martin, Billy R.; Makriyannis, Alexandros

doi:10.1016/0091-3057(91)90355-6

Cited by 28 publications

(18 citation statements)

References 11 publications

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“…Optimal activity is obtained with a seven or eight carbon length substituted with 1′,1′-or 1′,2′-dimethyl groups as was first demonstrated by Adams (e.g. 2) [52][53][54], while incorporation of halogen, cyano or azido group at the end of the side chain enhances CB1 affinity [55][56][57][58][59][60]. Thus, AM087 (3a) and O-581 (3b) bearing bromo and cyano substituents respectively at the end of the dimethylpentyl side chain exhibit subnanomolar affinities for the CB1 receptor.…”

Section: Classical Cannabinoidsmentioning

confidence: 96%

CB1 Cannabinoid Receptor Ligands

Thakur¹,

Nikas²,

Makriyannis³

2005

MRMC

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The CB1 receptor is expressed in the central nervous system and numerous other tissues including heart, lung and uterus and has been recognized as an important therapeutic target for pain, appetite modulation, glaucoma, multiple sclerosis and other indications. An interesting feature of this GPCR is its ability to be activated by a number of structurally different classes of compounds, thus, raising the possibility of multiple activated forms of the receptor. Understanding of the structure-activity relationships of cannabinergic ligands has paved the road for the development of novel ligands exhibiting receptor subtype selectivity and efficacy. This review highlights the important CB1 cannabinergic ligands developed to date.

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Section: Classical Cannabinoidsmentioning

confidence: 96%

CB1 Cannabinoid Receptor Ligands

Thakur¹,

Nikas²,

Makriyannis³

2005

MRMC

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“…(-)-5'-Bromo-∆ 8 -tetrahydrocannabinol 17a served also as a starting point for the synthesis of (-)-5'-iodo-∆ 8 -tetrahydrocannabinol 17b by following a reported procedure 11 and its modification. 19 The (-)-11-bromo-∆ 8 -tetrahydrocannabinol acetate 22 was the key intermediate in the synthesis of (-)-11-fluoro-∆ 8 - tetrahydrocannabinol 23 (Scheme 4). Compound 22 was prepared in 2 steps starting from (-)-∆ 9(11) -tetrahydrocannabinol 21 following a previously reported procedure.…”

Section: Synthesismentioning

confidence: 99%

“…A description of the in vivo pharmacology of several analogs described here (Table 1) has already been reported in our preliminary communications. 19,20 In this work we include the synthetic procedures for the analogs described here and extend our SAR studies to include new derivatives. Evaluation of the affinities of these halogenated cannabinoids allowed us to develop a suitable pharmacophore model for the CB1 receptor.…”

Section: Introductionmentioning

confidence: 99%

The role of halogen substitution in classical cannabinoids: A CB1 pharmacophore model

Nikas

Grzybowska

Papahatjis

et al. 2004

AAPS J

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The presence of halogens within the classical cannabinoid structure leads to large variations in the compounds' potencies and affinities for the CB1 receptors. To explore the structure activity relationships within this class of analogs we have used a series of halogen-substituted (-)-∆ 8 -tetrahydrocannabinol analogs and compared their affinities for the CB1 cannabinoid receptor. Our results indicate that halogen substitution at the end-carbon of the side chain leads to an enhancement in affinity with the bulkier halogens (Br, I) producing the largest effects. Conversely, 2-iodo substitution on the phenolic ring leads to a 2-fold reduction in affinity while iodo-substitution in the C1'-position of the side chain lowers the compound's affinity for CB1 by more than 8-fold. The pharmacophoric requirements resulting from halogen-substitution are explored using computer modeling methods.

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“…The side chain seems to be a place of choice for halogen substitution and a considerable enhancement in affinity for CB1 was observed by substitution at the terminal carbon of the side chain with bulkier halogens (Br, I) producing the largest effects (Charalambous et al, 1991a;Martin et al, 1993;Nikas et al, 2004). Thus, the 5V-Br-D 8 -THC and 5V-Br-1V,1V-dimethylpentyl-D 8 -THC (AM087, 28, Fig.…”

Section: Effects Of Side Chain Substituentsmentioning

confidence: 95%