Side chain methyl analogues of Δ8-THC

Huffman, John W.; Lainton, Julia A.H.; Banner, W. K.; Duncan, Sammy G.; Jordan, Robert D.; Yu, Shu; Dai, Dong; Martin, Billy R.; Wiley, Jenny L.; Compton, David R.

doi:10.1016/s0040-4020(96)01134-9

Cited by 25 publications

(8 citation statements)

References 25 publications

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“…A systematic study of methylated Δ8-THC analogs (entries 10–16 ) revealed 1' and 2' substitutions to be optimal, with a slight decrease in affinity in 3'-methyl analogs 14–15 and a sharp decrease in 4'-methyl analog 16 , with little difference in affinity observed between the R and S isomers. 86 Given the near doubling of receptor affinity by the 7-carbon chain analog 8 , a similar study of compounds with a 7-carbon alkyl chain, entries 17–27 , showed a similar trend, although less pronounced than the 5-carbon chain analogs. 87 Again, there were minimal differences between R and S isomers, with binding affinity optimal at the 1' and 2' positions in 17–20 , slowly decreasing as the methyl substitutions is moved down the alkyl chain (entries 21–27 ).…”

Section: Synthetic Classical Cannabinoidsmentioning

confidence: 91%

“…98 The addition of a more polar carboxyl group (81) causes a significant loss in CB1 affinity to 222 ± 63 nM, while retaining CB2 affinity at 4.00 ± 1.35 nM. Using substituted carboxamide groups (82)(83)(84)(85)(86), with the exception of 85, shows similarly high affinities for both receptors. Removing the carboxamide linker and directly coupling a heterocycle to the alkyl chain is not detrimental to binding affinity, as seen in morpholine 87 and imidazole 88.…”

Section: Synthetic Classical Cannabinoidsmentioning

confidence: 99%

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The Structure–Function Relationships of Classical Cannabinoids: CB1/CB2 Modulation

Bow

Rimoldi

2016

Perspect Medicin Chem

100

111

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The cannabinoids are members of a deceptively simple class of terpenophenolic secondary metabolites isolated from Cannabis sativa highlighted by (−)-Δ9-tetrahydrocannabinol (THC), eliciting distinct pharmacological effects mediated largely by cannabinoid receptor (CB1 or CB2) signaling. Since the initial discovery of THC and related cannabinoids, synthetic and semisynthetic classical cannabinoid analogs have been evaluated to help define receptor binding modes and structure–CB1/CB2 functional activity relationships. This perspective will examine the classical cannabinoids, with particular emphasis on the structure–activity relationship of five regions: C3 side chain, phenolic hydroxyl, aromatic A-ring, pyran B-ring, and cyclohexenyl C-ring. Cumulative structure–activity relationship studies to date have helped define the critical structural elements required for potency and selectivity toward CB1 and CB2 and, more importantly, ushered the discovery and development of contemporary nonclassical cannabinoid modulators with enhanced physicochemical and pharmacological profiles.

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Section: Synthetic Classical Cannabinoidsmentioning

confidence: 91%

Section: Synthetic Classical Cannabinoidsmentioning

confidence: 99%

The Structure–Function Relationships of Classical Cannabinoids: CB1/CB2 Modulation

Bow

Rimoldi

2016

Perspect Medicin Chem

100

111

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“…201 Structure−activity relationship (SAR) studies on synthetic Δ 8 -THC analogues varying both the length and substitution pattern of the side chain have been reported. 202 Side chains of five to eight carbon units were found to be optimal for CB1 activity. C7 and C8 analogues generally showed the strongest binding affinity to CB1 in the single digit to subnanomolar range.…”

Section: ■ Cannabichromenementioning

confidence: 99%

Phytocannabinoid Pharmacology: Medicinal Properties of Cannabis sativa Constituents Aside from the “Big Two”

Sampson¹

2020

J. Nat. Prod.

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Plant-based therapies date back centuries. Cannabis sativa is one such plant that was used medicinally up until the early part of the 20th century. Although rich in diverse and interesting phytochemicals, cannabis was largely ignored by the modern scientific community due to its designation as a schedule 1 narcotic and restrictions on access for research purposes. There was renewed interest in the early 1990s when the endocannabinoid system (ECS) was discovered, a complex network of signaling pathways responsible for physiological homeostasis. Two key components of the ECS, cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), were identified as the molecular targets of the phytocannabinoid Δ9-tetrahydrocannabinol (Δ9-THC). Restrictions on access to cannabis have eased worldwide, leading to a resurgence in interest in the therapeutic potential of cannabis. Much of the focus has been on the two major constituents, Δ9-THC and cannabidiol (CBD). Cannabis contains over 140 phytocannabinoids, although only a handful have been tested for pharmacological activity. Many of these minor cannabinoids potently modulate receptors, ionotropic channels, and enzymes associated with the ECS and show therapeutic potential individually or synergistically with other phytocannabinoids. The following review will focus on the pharmacological developments of the next generation of phytocannabinoid therapeutics.

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“…This branching was next realized on D 9 -THC and D 8 -THC [55] [56]. Of the two C(1')-methyl isomers, the (R)-isomer exhibited higher CB 1 affinity (K i (CB 1 ) ¼ 7.6 nm) compared with the (S)-isomer (K i (CB 1 ) ¼ 20 nm) [58]. Although all four stereoisomers are very potent cannabinoids ligands, the (1'S,2'R)-isomer 7 possesses the highest affinity for the CB 1 cannabinoid receptor [57].…”

Section: 1mentioning

confidence: 92%

“…Each of these eight stereoisomers was later individually synthesized, and pharmacological studies showed that only two of them were very potent [54]. The stereochemical features of an alkyl substituent on the alkyl side chain were further explored in a series of compounds bearing only one methyl group at either the C(1'), C(2'), C(3'), or C(4') of the side chain [58]. This substitution pattern of the side chain introduces two additional stereogenic centers.…”

Section: 1mentioning

confidence: 99%

Medicinal Chemistry Endeavors Around the Phytocannabinoids

Stern

Lambert

2007

ChemInform

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Over the past 50 years, a considerable research in medicinal chemistry has been carried out around the natural constituents of Cannabis sativa L. Following the identification of D 9 -tetrahydrocannabinol (D 9 -THC) in 1964, critical chemical modifications, e.g., variation of the side chain at C(3) and the opening of the tricyclic scaffold, have led to the characterization of potent and cannabinoid receptor subtype-selective ligands. Those ligands that demonstrate high affinity for the cannabinoid receptors and good biological efficacy are still used as powerful pharmacological tools. This review summarizes past as well as recent developments in the structure -activity relationships of phytocannabinoids.

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Side chain methyl analogues of Δ8-THC

Cited by 25 publications

References 25 publications

The Structure–Function Relationships of Classical Cannabinoids: CB1/CB2 Modulation

The Structure–Function Relationships of Classical Cannabinoids: CB1/CB2 Modulation

Phytocannabinoid Pharmacology: Medicinal Properties of Cannabis sativa Constituents Aside from the “Big Two”

Medicinal Chemistry Endeavors Around the Phytocannabinoids

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